Dolichol deprivation theory

[tryingnottoworry]

[Size=4]The Dolichol Deprivation Theory[/size]

What is the dolichol deprivation theory? It is the theory that our syndrome is caused by the inhibition of SRD5A3 (in addition to SRD5A2) by finasteride, dutasteride, and/or saw palmetto.

5 alpha reductase type 3 (SRD5A3) and its function was recently discovered, and it was also discovered only last year that finasteride inhibits SRD5A3 about the same as 5 alpha reductase type 2. SRD5A3’s primary function is to synthesize a special sort of alcohol called “dolichol” which is used in protein folding within the endoplasmic reticulum of cells for the very beginning stages of glycosylation, and also has a role in DHT production. Glycosylation is an extremely important cellular process which is both upstream and the precursor to proper function of the higher functions of the body (including thyroid function, liver function, hormone function, and many more). Disruption of the glycosylation process can affect almost every system in the body, and can cause a cascade reaction causing a multitude of system-wide dysfunctions, including endocrinopathies (dysfunctional endocrine system), secondary hypogonadism, small testicles, muscle weakness, muscle atrophy, poor motor skills, stroke-like episodes (e.g. brain fog), cognitive impairment, speech difficulties, vitamin D deficiency, and many more.

Until we have a proper laboratory study performed, we won’t know exactly how SRD5A3 inhibition by finasteride ultimately affects us, but based off of research currently available, it may potentially happen like this: Finasteride inhibits 5 alpha reductase type 3 > Inhibited SRD5A3 inhibits dolichol production > Endoplasmic Reticulum becomes stressed due to incompetent protein folding due to dolichol deprivation > ER initiates the Unfolded Protein Response due to overwhelming stress caused by too many unfolded proteins > UPR causes upregulation of gene expressions associated in dolichol production (such as the GlcNAc-1-P transferase (GPT) gene) > overexpressed GPT gene hinders Lec35 gene product (Lec35p) > hindered Lec35p causes inefficient utilization of dolichol (yet dolichol and Lec35p levels remain normal) > inefficient utilization of dolichol stresses the ER and continues the loop > this causes a psuedo-congenital disorder of glycosylation.

5 alpha reductase type 2 has been, for the longest time, the focal point of our research and understanding of PFS, but it isn’t until now that we can see the effects of inhibiting 5 alpha reductase type 3. Unlike what most other theories suggest, a glycosylation disorder would be our “root” cause, as it is upstream of basically every higher function in the body, including cortisol production, thyroid function, liver function, hormone function, and nearly everything else. Every other theory may address the cause of our symptoms, but what’s causing the cause? Understanding the effects of the inhibition of SRD5A3 through the actions of finasteride may be the key to understanding the scope of the post finasteride syndrome.

[Size=4]Relevant Scientific Research[/size]

[Size=4]Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride[/size]

We found that SRD5a-3 is highly sensitive to finasteride and dutasteride and shows similar sensitivity as SRD5a-2 for finasteride, while it is much more sensitive to dutasteride. The enzyme is highly expressed in the human skin, brain, mammary gland and breast cancer cells. Our data strongly suggest that SRD5a-3 could be the main enzyme responsible for 5areductase activity, previously believed to be associated with SRD5a-1, in many tissues and cell lines.

[Size=4]SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.[/size]

We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation…

[Size=4]Dolichol Inhibition[/size]

Dolichols are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability of dolichols can affect every cellular process in the body.
Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense.

[Size=4]Unexpected Basis for Impaired Glc3Man9GlcNAc2-P-P-Dolichol Biosynthesis by Elevated Expression of GlcNAc-1-P Transferase[/size]

By compensatory overexpression of Lec35p, G3M9Gn2-P-P-Dol synthesis in GPT overexpressers could be restored. However, GPT overexpression did not affect the levels of Lec35 mRNA or protein. These results suggest that GPT may impair Lec35p function, and imply that upper as well as lower limits on GPT expression exist in normal cells. Since the mammalian GPT gene can undergo spontaneous amplification, the data also indicate a potential basis for forms of pseudo-CDG-If…

…In humans, this might be predicted to cause a nonheritable pseudo-CDG-If mosaic phenotype. These would escape detection by standard sequence-based screening of blood cells of unclassified CDG-I patients because the phenotype would not necessarily be expressed in blood cells, and sequences of GPT DNA and RNA would appear normal.

[Size=4]Inherited Glycosylation Disorder: Researchers Find Cause of Metabolic Disease – And Possible Cure[/size]

Writing in the July 15 online edition of the journal Cell, Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, with Lihadh Al-Gazali, a professor of pediatrics and pathology at United Arab Emirates University, and colleagues discovered that the gene SRD5A3 is responsible for the synthesis of a lipid used by cells as a sugar carrier for protein glycosylation – a complicated, multi-part process in which proteins are modified by the addition of a sugar or sugar chain. Without the added sugars, proteins do not fold or fold incorrectly, resulting in dysfunction and disease…

…“The key was identifying the enzyme’s role in producing dolichol. This is the basic step that is blocked in our patients, and the disease is the result. Our idea is that if you feed these patients dolichol, that might just treat the condition. It would be similar to giving insulin to diabetics. It’s a simple solution, but one nobody had thought of.”…

…Currently, artificially produced dolichol is very expensive, mostly because there hasn’t been much demand for it, but the researchers note that the compound is naturally abundant in some plants, such as the gingko or maidenhair tree and spinach. “Ginkgo is already the source of a lot of compounds, so getting dolichol might just mean another step in the extraction process. After that, you could develop a pill that patients could take as a supplement to their diet.”

[Size=4]Glossary:[/size]

SRD5A1- Steroid 5-alpha-reductase type 1, also known as 5AR1. This enzyme converts testosterone into dihydrotestosterone (DHT), and is weakly inhibited by Finasteride.

SRD5A2 - Steroid 5-alpha-reductase type 2, also known as 5AR2. This enzyme converts testosterone into dihydrotestosterone (DHT), and is potently inhibited by Finasteride.

SRD5A3 - Steroid 5-alpha-reductase type 3, also known as 5AR3. This enzyme converts polyprenol into dolichol for use in N-Glycosylation, and also has a role in DHT production. SRD5A3 is potently inhibited by Finasteride.

Finasteride - Designed to be a SRD5A2 inhibitor, it was recently discovered to also potently inhibit SRD5A3.

Dutasteride - Designed to be an SRD5A1 and SRD5A2 inhibitor, it was recently discovered to inhibit SRD5A3 with extreme potency, roughly 50 times more than finasteride.

Saw Palmetto - A natural SRD5A1 and SRD5A2 inhibitor. Due to a lack of research it is unknown to what extent saw palmetto has on SRD5A3, but due to it’s similarity to the actions of dutasteride (though much weaker), it is likely to inhibit SRD5A3 at least as much as finasteride, if not more.

Ropren - An experimental Polyprenol/Dolichol supplement.

Polyprenol - A type of alcohol, and the precursor to dolichol. Polyprenol is converted into dolichol by SRD5A3.

Dolichol - A type of alcohol, and a necessary component of N-Glycosylation. Dolichol synthesis is dependent on the functionality of SRD5A3, and the depletion of dolichol leads to the disruption of glycosylation and subsequent diseases.

Glycosylation - is the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells (along with DNA, RNA, and proteins). Glycosylation is performed in several stages, such as N-linked and O-linked glycosylation. Disruption of glycosylation leads to congenital disorders of glycosylation (CDG), and near or complete shut down of glycosylation is lethal.

N-linked Glycosylation: Also known as N-Glycosylation, and is the beginning step in glycosylation, and is involved with folding eukaryotic proteins. N-Glycosylation occurs within the endoplasmic reticulum (ER) of cells.

O-linked Glycosylation: Also known as O-Glycosylation, and is the next phase of glycosylation, after N-Glycosylation. O-Glycosylation occurs within the golgi apparatus.

Glycoproteins - The product of glycosylation, glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification.

Endoplasmic Reticulum (ER) - The ER is a eukaryotic organelle that forms an interconnected network of tubules, vesicles, and cisternae within cells. Rough endoplasmic reticula synthesize proteins, while smooth endoplasmic reticula synthesize lipids and steroids, metabolize carbohydrates and steroids (but not lipids), and regulate calcium concentration, drug detoxification, and attachment of receptors on cell membrane proteins.

Golgi Apparatus - The Golgi Apparatus (also Golgi body or the Golgi complex) is an organelle found in most eukaryotic cells. It processes and packages macromolecules, such as proteins and lipids, after their synthesis and before they make their way to their destination; it is particularly important in the processing of proteins for secretion. The Golgi apparatus forms a part of the cellular endomembrane system.

Congenital Disorders of Glycosylation (CDG) - A CDG is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. The majority of CDGs are caused by a disruption in the dolichol pathway.

Pseudo CDG - An non-inheritable acquired version of a CDG. While not a true CDG, it may share many of the same characteristics.

The Unfolded Protein Response (UPR) - The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis).

GlcNAc-1-P transferase gene (GPT) - GPT catalyzes the first and committed step in the dolichol cycle, thus playing a fundamental role in the pathway for protein N-glycosylation. It also has upper and lower limits of expression, and if overexpressed, has the potential to hinder Lec35p.

Lec35 gene product (Lec35p) - Lec35p required for utilization of the mannose donor mannose-P-dolichol (MPD) in synthesis of both lipid-linked oligosaccharides (LLOs) and glycosylphosphatidylinositols, which are important for functions such as protein folding and membrane anchoring, respectively. Hinderance of Lec35p can cause a psuedo-CDG which is undetectable by conventional CDG blood screening.

Spinach - A delicious dark green leafy vegetable rich in dolichol.

[Size=4]The Spinach Diet[/size]

This is the first treatment based off of the dolichol deprivation theory. If the inhibition of SRD5A3 (and subsequent dolichol deprivation) was indeed what caused our syndrome, then by increasing our dolichol levels the point of overcompensating, we could theoretically lessen the stress on the ER. If the stress on the ER caused a UPR to induce a persistent overexpression of the GPT gene, then by lessening the stress on the ER, it could potentially convince the ER to cause a persistent normal expression of the GPT gene, which could potentially lead to the resolution of our syndrome. Unfortunately the only dolichol supplement currently available “Ropren” is extremely expensive and not readily available, so we would have to seek an alternative source. Spinach is one of the few natural sources of dolichol, so the spinach diet treatment was formed.

If you would like to try the spinach diet, here’s what you’ll need to do: Eat a bag (about 170g) of raw uncooked spinach a day, every day. If possible, get organic spinach. Continue eating your spinach once a day for at least a month. When you decide to start weening off, eat about 3/4th of a bag for about 4 days, then 1/2 a bag for 4 days, then 1/4th for 4 days, and finally 1/8th for 4 days.

Keep in mind that everyone’s body is different, so don’t go into this expecting a miracle. To put it in perspective, it’s trying to treat a supposed glycosylation disorder with food. There is evidence that it has the potential to help, but it all comes down to how your body was broken, and what it needs to be fixed.

FAQ coming soon.

[tryingnottoworry]

[Size=4](Below here is where the topic began back in March of 2011)[/size]

I’ve been looking at various research sites about the effects of finasteride, and found some very interesting information about the importance of dolichol. (I also searched our forum for any previous discussions about dolichol without any results).

We get our dolichol production/conversion through our 5 alpha-reductase type 3 enzyme (SRD5a-3). Dolichol is vital for producing glycoproteins. Glycoproteins have a hormone function in the HCG and TSH. Disrupting glycoprotein synthesis can cause a dysfunction of almost any cellular process. Finasteride inhibits 5 alpha-reductase type 3 roughly the same as 5 alpha-reductase type 2. I would theorize that by inhibiting 5ar3 (in addition to type 2), our body becomes depraved of dolichol production, which in turn sets off a chain reaction.

Here are my references:

http://www.ncbi.nlm.nih.gov/pubmed/20637498

We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

http://www.genecards.org/cgi-bin/carddisp.pl?gene=Srd5a3&snp_show_mode=1&snp=42

steroid 5 alpha-reductase 3
Function: Probable polyprenol reductase. Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol. Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation. Probably acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism. Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT)

http://en.wikipedia.org/wiki/Human_chorionic_gonadotropin

Glycoproteins have a hormone function in the Human chorionic gonadotropin (HCG) and thyroid-stimulating hormone (TSH)

http://en.wikipedia.org/wiki/Mevalonate_inhibition#Dolichol_Inhibition

Dolichols are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability of dolichols can affect every cellular process in the body.

Potential side effects from altered glycoprotein synthesis include impairment of DNA error correction, dysfunction of almost any cellular process, altered cell identification, altered cell messaging, and altered immunodefense.

http://www.researchgate.net/publication/5861012_Novel_5_alpha-steroid_reductase_%28SRD5A3_type-3%29_is_overexpressed_in_hormone-refractory_prostate_cancer

Knockdown of SRD5A3 expression by small interfering RNA in prostate cancer cells resulted in a significant decrease in DHT production and a drastic reduction in cell viability. These findings indicate that a novel type 3 5 alpha-steroid reductase, SRD5A3, is associated with DHT production and maintenance of androgen-androgen receptor-pathway activation in HRPC cells, and that this enzymatic activity should be a promising molecular target for prostate cancer therapy.

http://www.deepdyve.com/lp/de-gruyter/human-type-3-5-reductase-is-expressed-in-peripheral-tissues-at-higher-HwVY3MbV0i?autoClickRent=true (actual article, but you have to pay to see all of it)

http://related.springerprotocols.com/lp/de-gruyter/human-type-3-5-reductase-is-expressed-in-peripheral-tissues-at-higher-HwVY3MbV0i (unformatted version, but you can read the whole article)

We found that SRD5a-3 is highly sensitive to finasteride and dutasteride and shows similar sensitivity as SRD5a-2 for finasteride, while it is much more sensitive to dutasteride. The enzyme is highly expressed in the human skin, brain, mammary gland and breast cancer cells. Our data strongly suggest that SRD5a-3 could be the main enzyme responsible for 5areductase activity, previously believed to be associated with SRD5a-1, in many tissues and cell lines.

I hope this leads to something that can help us. I’ll keep praying for you guys.

Crosspost from The cure for brain fog: pregnenolone thread

@Mew

I have done some digging but have not been able to find anything linking drug to Congenital Adrenal Hyperplasia, which is present from birth due to genetic defect and typically involves women ie, hirsutism (excessive body hair, increased androgen production)… although, in men it can cause hypogonadism as well. Info: caresfoundation.org/productcart/pc/rare_forms_cah.html

I’ve got a connection to consider:

• Congenital Adrenal Hyperplasia is caused by the disruption of cortisol production. - source
• 5 alpha reductase type 3 (SRD5A3) produces dolichol. - source
• Dolichol is synthesized through the same path as cholesterol. - source 1 source 2
• Cholesterol is required for cortisol synthesis. - source
• Finasteride inhibits 5 alpha reductase type 3 - (about the same as type 2). - source
• You could theorize that by inhibiting SRD5A3, therefore the production/synthesis of dolichol, it could disrupt the synthesis of cholesterol - source (page 316) - into cortisol, and potentially causing a similar CAH condition such as Lipoid congenital adrenal hyperplasia

Another possibility (or combination of the two) would be the direct effects of dolichol/N-glycosylation deprivation, which could potentially lead to a similar condition of Congenital Disorder of Glycosylation. It lists “fluctuating hormone levels (e.g.prolactin, FSH and GH)” as a symptom, which sounds similar to what PFS does.

[tryingnottoworry]

Looking further into this, it appears the Dolichol Deprivation Theory fits quite well with the Androgen Insensitivity Syndrome theory, as Lipoid congenital adrenal hyperplasia is listed as one of the types of AIS.

The article also lists that as of 2010, there are over 400 AR mutations on record. Could it be possible that the reason WE’RE the ones who’re suffering from Fin sides (as opposed to the majority of fin users) is because we each carry some form of mutant gene that is vulnerable to different aspects of dolichol deprivation? It would also explain why we don’t all have the same symptoms, why we all improve/decline/stagnate at different rates, and why we all have such wildly different results from the same treatment.

Could this be it? Could this be what we’ve been up against this whole time?

[Y-C]

@tryingnottoworry

Could this be it? Could this be what we’ve been up against this whole time?

I sure hope not, because there is absolutely no treatment possible.

And besides, that still doesn’t explain why the effects are all fully pronounced when the treatment is stopped.

[tryingnottoworry]

I wouldn’t say it would be incurable, as this wouldn’t imply we actually HAD Lipoid congenital adrenal hyperplasia, just similar aspects of it. We had a good working system, and our bodies are fully developed, unlike the children born with that condition. We have hope, and we can (just as others have) recover.

And I’m not a doctor, I can’t explain all of the intricacies of what this could all mean. The scope of this theory does not yet cover the chronological progression of symptoms, as a medical professional/researcher would have to study it.

[tryingnottoworry]

I found something new that may tie into all of this.

http://glycob.oxfordjournals.org/content/18/1/125.abstract

GlcNAc-1-P transferase (GPT) transfers GlcNAc-1-P from UDP-GlcNAc to dolichol-P (Dol-P), forming GlcNAc-P-P-Dol to initiate synthesis of the lipid-linked oligosaccharide Glc3Man9GlcNAc2-P-P-dolichol (G3M9Gn2-P-P-Dol). Elevated expression of GPT in CHO-K1 cells is known to cause accumulation of the intermediate M5Gn2-P-P-Dol, presumably by excessively consuming Dol-P and thereby hindering Dol-P-dependent synthesis of Man-P-Dol (MPD) and Glc-P-Dol (GPD), which provide the residues for extending M5Gn2-P-P-Dol to G3M9Gn2-P-P-Dol. If so, elevated GPT expression should increase oligosaccharide-P-P-Dol quantities and reduce monosaccharide-P-Dol quantities, while requiring GPT enzymatic activity. Here we report that elevated GPT expression failed to appreciably alter the quantities of the two classes of dolichol-linked saccharide, and that neither a GPT inhibitor nor introduction of an inactivating mutation into GPT prevented M5Gn2-P-P-Dol accumulation, arguing against excessive Dol-P consumption. Unexpectedly, we noticed similarities between the phenotypes of GPT overexpressers and of CHO-K1 cells lacking Lec35p (encoded by MPDU1, the congenital disorder of glycosylation (CDG)-If locus), which is required for utilization of MPD and GPD. By compensatory overexpression of Lec35p, G3M9Gn2-P-P-Dol synthesis in GPT overexpressers could be restored. However, GPT overexpression did not affect the levels of Lec35 mRNA or protein. These results suggest that GPT may impair Lec35p function, and imply that upper as well as lower limits on GPT expression exist in normal cells. Since the mammalian GPT gene can undergo spontaneous amplification, the data also indicate a potential basis for forms of pseudo-CDG-If.

So if I am understanding this correctly, it means that GPT overexpression can cause impairment of Lec35p function, without necessarily reducing the level of Lec35p. If Lec35p is impaired by the spontaneous amplification of the GPT gene, it can potentially cause a psuedo-Congenital Disorder of Glycosylation, which mirrors many of our PFS side effects. By compensatory overexpression of Lec35p, G3M9Gn2-P-P-Dol synthesis in GPT overexpressers could be restored.

Is it possible that Finasteride, by inhibiting 5 alpha reductase type 3, thereby inhibiting dolichol synthesis, caused our bodies to compensate by overexpressing our GPT gene? Then perhaps when the drug left our bodies, the balance the GPT tried to compensate with turned into an imbalance of overcompensation once SRD5A3 came back online, due to the gene refusing to underexpress itself, leading to psuedo-CDG. Maybe the two weeks grace before the crash is the return of dolichol synthesis, only to be crushed by the heightened overexpression of the GPT attempting to maintain the same balance it had when dealing with finasteride.

Could the cure for this be compensatory overexpression of Lec35p? HMMMMMMMM.

[191]

Our symptoms do not match up with disorders of glycosylation.

[tryingnottoworry]

ncbi.nlm.nih.gov/pubmed/17639595

Congenital disorders of glycosylation (CDG) are a group of metabolic disorders resulting from defective synthesis of N-linked oligosaccharides. CDG-Ia is the most common of the 21 known types defined by defects in different steps of the synthetic pathway. An increasing number of American adults with CDG-Ia are being recognized but little is documented on the morbidity and mortality in this population. These adults have moderate mental retardation, ataxia, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, and endocrinopathies. Four adults with CDG-Ia, ages 19-36 years old are presented. All are active, dysarthric conversant adults with moderate cognitive impairment. They are ataxic and wheelchair dependent, however, only the oldest man shows significant muscle atrophy. All have diagnosed peripheral neuropathy. Three of four remain on anticonvulsants with only occasional seizures, none have had stroke-like episodes since their teen years. Their skeletal issues include significant kyphoscoliosis, joint contractures, and osteopenia. Retinitis pigmentosa and myopia complicate their functional vision. The women do not menstruate and the men have small testes resulting from hypogonadotropic hypogonadism. Documentation of clinical complications and successful management strategies in adults with CDG will improve their quality of life and allow more informed prognostic discussions with families of younger affected individuals.

These are people who were born with congenital disorder of glycosylation, they were stunted during development and have a defective system. We do not have this condition, but we may share some similarities due to the similar action of SRD5A3 suppression (and possibly a relation to congenital adrenal hyperplasia).

[tryingnottoworry]

Holy crap, more evidence!

http://www.sciencedaily.com/releases/2010/07/100715142439.htm

Inherited Glycosylation Disorder: Researchers Find Cause of Metabolic Disease – And Possible Cure
ScienceDaily (July 15, 2010) — An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, has discovered the gene mutation responsible for a condition in which eye and brain development is severely disrupted in affected infants.

They also suggest a potential remedy that would involve a simple, daily dietary supplement.
The condition is one of the congenital disorders of glycosylation or CDG, a group of syndromes in which inborn metabolic errors result in serious, sometimes fatal, malfunctions of different organ systems, especially the nervous system, muscles and intestines. Children and adults with CDG have varying degrees of disability, including cognitive impairment and speech difficulties, poor motor skills, vision problems and stroke-like episodes. CDG is rare, but for most of the disorders, there is no treatment.
Writing in the July 15 online edition of the journal Cell, Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, with Lihadh Al-Gazali, a professor of pediatrics and pathology at United Arab Emirates University, and colleagues discovered that the gene SRD5A3 is responsible for the synthesis of a lipid used by cells as a sugar carrier for protein glycosylation – a complicated, multi-part process in which proteins are modified by the addition of a sugar or sugar chain. Without the added sugars, proteins do not fold or fold incorrectly, resulting in dysfunction and disease.
The UCSD work revealed the molecular basis of an essential, but mysterious, enzymatic reaction in protein glycosylation. “We found the long-sought polyprenol reductase that has been suspected for decades” said Gleeson, a Howard Hughes Medical Institute Investigator who supervised the research. “Using a human genetic approach, we were able to not only find a clue to understand this class of disorder, but also to solve a basic science problem.”
After translation, many proteins are modified with the addition of glycans (polysaccharides or oligosaccharides) that are necessary to help them perform their functions. This modification occurs in a specific cell compartment – the membrane of the endoplasmic reticulum – where the glycans are transported by a lipid before transferring onto proteins.
Dolichol is the lipid carrier for glycans used during protein glycosylation; its availability is critical to accomplishing the modification process, but the synthesis or production of dolichol was poorly understood, especially the last step when polyprenol, a natural long-chain alcohol, is reduced to create dolichol.
“Dolichol is used by the cell like a truck to transport glycans to their destination but also as a support to build them” said Vincent Cantagrel, a UC San Diego postdoctoral fellow and study co-author. “A defect in this transportation results in a less efficient process of glycosylation. Some proteins will miss some glycan chains and will not function correctly.”
In CDG cases, the conversion from polyprenol to dolichol is blocked by a mutation in the SRD5A3 gene. “The mutation is inherited recessively,” said Gleeson. “Both parents must pass along a mutated copy, which is why you don’t see it so much in the US. However, in the Middle East, where marriage of cousins is common, these diseases are much more prevalent.”
Identifying the blockage, Gleeson said, pointed to a possible treatment.
“The key was identifying the enzyme’s role in producing dolichol. This is the basic step that is blocked in our patients, and the disease is the result. Our idea is that if you feed these patients dolichol, that might just treat the condition. It would be similar to giving insulin to diabetics. It’s a simple solution, but one nobody had thought of.”
Currently, artificially produced dolichol is very expensive, mostly because there hasn’t been much demand for it, but the researchers note that the compound is naturally abundant in some plants, such as the gingko or maidenhair tree and spinach. “Ginkgo is already the source of a lot of compounds, so getting dolichol might just mean another step in the extraction process. After that, you could develop a pill that patients could take as a supplement to their diet.”
Gleeson and colleagues are now testing their idea with animal models.
While CDG cases are rare, Gleeson and Cantagrel said their discovery about the polyprenol-dolichol block in the glycosylation process has broader ramifications.
Glycosylation is essential to the normal growth and function of all tissues and organs. “If we look at other steps along the glycosylation pathway, it’s possible we can find other break points,” Gleeson said. “We might be able to treat or cure other forms of CDG or even more common diseases that use this pathway, such as cirrhosis, in which there is deficiency of dolichol.”

[Size=4]This article directly links disabled SRD5A3/dolichol activity to congenital disorders of glycosylation!!![/size]

They also theorize that if you suppliment dolichol it could help treat the condition, however I’m not sure if that would relate to us in the same way. Considering we (PFS sufferers, not CDG sufferers) should still have a functioning SRD5A3 enzyme (as finasteride is no longer inhibiting it), our body’s use of dolichol is most likely being disrupted further down the line, probably by an overexpressed GPT gene which is inhibiting Lec35p, causing a psudeo version of CDG. They also suggested that they may be able to find other “break points” along the glycosylation pathway. Cortisol is synthesized through the same pathway as dolichol, which could explain a connection to psuedo-lipoid congenital adrenal hyperplasia.

Just for reference, here’s a list of some of the symptoms that correlate between congenital disorders of glycosylation and our post finasteride syndrome:
• endocrinopathies (dysfunctional endocrine system)
• secondary hypogonadism
• small testicles
• muscle weakness
• muscle atrophy
• poor motor skills
• stroke-like episodes (e.g. brain fog)
• cognitive impairment
• speech difficulties

These articles about SRD5A3 and its impact on dolichol have just come out within the past year or two, including the fact that finasteride inhibits it. I think this mystery may be finally coming to an end, and hopefully we can be cured of this accursed syndrome once and for all.

[tryingnottoworry]

Everything just keeps falling into place. Let’s put it all together:

[Size=4]5alpha-reductase type 3 (SRD5A3)[/size]

We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

So we have this enzyme that makes dolichol. What is dolichol?

[Size=4]Dolichol[/size]

Dolichols play a role the co-translational modification of proteins known as N-glycosylation in the form of dolichol phosphate. Dolichols function as a membrane anchor for the formation of the oligosaccharide Glc3-Man9-GlcNAc2 (where Glc is glucose, Man is mannose, and GlcNAc is N-acetylglucosamine). This oligosaccharide is transferred from the dolichol donor onto certain asparagine residues of newly forming polypeptide chains. Dolichol is also involved in transfer of the monosaccharides to the forming Glc3-Man9-GlcNAc2-Dolichol carrier.
In addition, dolichols can be adducted to proteins as a posttranslational modification, a process in which branched carbohydrate trees are formed on a dolichol moiety and then transferred to an assembly of proteins to form a large glycoprotein in the rough endoplasmic reticulum.
Dolichols are the major lipid component (14% by mass) of human substantia nigra (SN) neuromelanin.[1]

Dolichol is involved with protein folding and transfer inside of the endoplasmic reticulum (a “chaperone”). What is the endoplasmic reticulum?

[Size=4]Endoplasmic reticulum[/size]

The endoplasmic reticulum (ER) is a eukaryotic organelle that forms an interconnected network of tubules, vesicles, and cisternae within cells. Rough endoplasmic reticula synthesize proteins, while smooth endoplasmic reticula synthesize lipids and steroids, metabolize carbohydrates and steroids, and regulate calcium concentration, drug detoxification, and attachment of receptors on cell membrane proteins. Sarcoplasmic reticula solely regulate calcium levels.

The endoplasmic reticulum is a super-complicated cellular system that creates/transfers proteins, and affects darn near everything.

What happens if your SRD5A3 gets shut down and your cells get deprived of dolichol?

Dolichols are isoprenoids synthesised from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuropeptides, cell identification, cell messaging and Immunodefence. Reduced bioavailability of dolichols can affect every cellular process in the body.

A lot of bad stuff can happen! Well what does Finasteride do to your SRD5A3?

We found that SRD5a-3 is highly sensitive to finasteride and dutasteride and shows similar sensitivity as SRD5a-2 for finasteride, while it is much more sensitive to dutasteride. The enzyme is highly expressed in the human skin, brain, mammary gland and breast cancer cells. Our data strongly suggest that SRD5a-3 could be the main enzyme responsible for 5areductase activity, previously believed to be associated with SRD5a-1, in many tissues and cell lines.

Your SRD5A3 gets inhibited, drastically reducing your body’s production of dolichol and its ability to fold and transfer proteins. What does this do to the endoplasmic reticulum?

[Size=4]Perturbation of ER Function[/size] - Schröder M, Kaufman RJ. “The Mammalian Unfolded Protein Response”

Proper function of the ER is perturbed when the influx of nascent, unfolded polypeptide chain exceeds the folding capacity of the ER. This can be achieved by overexpressing large and heavily modified proteins, e.g., blood coagulation factor VIII (2, 3) or small and structurally simple proteins, such as antithrombin III (4). These proteins were found in a complex with ER resident molecular chaperones (2) or in high-molecular-weight aggregates (4). Expression of mutant, folding-incompetent proteins induced expression of ER resident molecular chaperones (5). This observation is the biochemical basis for a wide variety of diseases termed ER storage or conformational diseases (6, 7). Recent work showed that normal biological processes, such as differentiation of B cells into plasma cells (8), viral infection (9), and, in plants, the host’s response to a microbial infection (10, 11), are associated with increases in secretory activity that, at least in the early stages, exceed the folding capacity of the ER and cause a UPR

How does the endoplasmic reticulum attempt to cope with this?

[Size=4]Remedies of Perturbed ER Function[/size] - Schröder M, Kaufman RJ. “The mammalian unfolded protein response”

To bring the folding capacity of the ER in line with the folding demand placed on the ER, the folding demand is decreased, and the folding capacity of the ER increased (Figure 1). To decrease the folding demand, transcription of genes, encoding secretory proteins and translation (12), are down regulated; and the clearance of slowly folding or misfolded proteins through ER-associated degradation (ERAD) is increased (13). To increase the folding capacity of the ER, the synthesis of ER resident molecular chaperones and foldases is increased (5), and the ER increases in size (3) to dilute the increased unfolded protein load.

So the endoplasmic reticulum has the potential for adaptation. It also has the ability to the change transcription of genes (gene expression) if it needs to up or down regulate them. But in the absence of a normal supply of dolichol, proteins are being improperly folded and building up within the endoplasmic reticulum. What happens when the unfolded protein load goes beyond its manageable threshold?

[Size=4]The Unfolded Protein Response[/size]

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms. This article focuses on the mammalian response.
The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis).

Oh crap, a cellular time-bomb! Too many useless unfolded proteins are making the endoplasmic reticulum jam-packed! Your body is probably going through some crazy stuff right now. What happens from here on could lead to many different outcomes.

It’s plausible that the endoplasmic reticulum could overexpress the gene most associated with the initial usage of dolichol to allow it to handle the load. Alternatively it may underexpress it in order to slow production, allowing it time to eject its junk proteins. (a cellular biologist could probably explain this process better)

[Size=4]UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase gene (GPT)[/size]

The UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase catalyzes the first and committed step in the dolichol cycle, thus playing a fundamental role in the pathway for protein N-glycosylation.

So now the ER has ejected all of its bad proteins, what happens at this point? Things should return to normal… right?

Maybe not

Unexpectedly, we noticed similarities between the phenotypes of GPT overexpressers and of CHO-K1 cells lacking Lec35p (encoded by MPDU1, the congenital disorder of glycosylation (CDG)-If locus), which is required for utilization of MPD and GPD. By compensatory overexpression of Lec35p, G3M9Gn2-P-P-Dol synthesis in GPT overexpressers could be restored. However, GPT overexpression did not affect the levels of Lec35 mRNA or protein. These results suggest that GPT may impair Lec35p function, and imply that upper as well as lower limits on GPT expression exist in normal cells. Since the mammalian GPT gene can undergo spontaneous amplification, the data also indicate a potential basis for forms of pseudo-CDG-If.

It’s possible that after the UPR crash, the ER may have up-regulated GPT too far, thereby impairing Lec35p function, which in turn would create a pseudo-congenital disorder of glycosylation effect. Or maybe the UPR underexpressed GPT and never brought it back to normal, which would in turn starve your body of nutrients. It’s also possible something else further down the line may have been tweaked the wrong way, possibly causing some sort of psuedo-congenital adrenal hyperplasia.

If we could find what went wrong after the UPR, we’ll be another step closer to finding our cure.

[kazman]

tryingnottoworry, very interesting. Have been told by an andrologist that the existence of 5AR3 has not been confirmed/agreed to by those doing research in the area.

Here are some additional references that you might have missed (think you have most of these):

viewtopic.php?f=9&t=4875&p=34069#p34069

[tryingnottoworry]

Thanks Kazman, you’re awesome!

Have been told by an andrologist that the existence of 5AR3 has not been confirmed/agreed to by those doing research in the area.

Sounds rather reminiscent of what doctors say about PFS sufferers.

Everyday I keep finding more articles to study, and I’ve been writing them down as I go. However these 8-hour research marathons are starting to take a toll on me (I have a 9 hours a day, 6 days a week job), so I’m going to take a short break from doing this heavy-duty research, and pick it back up in a day or two after I get a proper night’s sleep. If anyone else wants to help me research this (especially someone with a cellular biology/genetics backround), please feel free.

So I’ve been looking into the effects of other drugs which inhibit dolichol, and found that statins (aka Lipitor), have been reported to cause symptoms that can be EXACTLY the same as ours. The site http://www.spacedoc.net/ is sort of like propeciahelp.com for statin sufferers, and they list: confusion, short term memory loss, depression, muscle pain, muscle damage, muscle weakness, chronic fatigue, insomnia, lack of libido, lack of emotions, erectile dysfunction, rashes, thyroid problems, vitamin D deficiency, and a whole bunch of other stuff. Statins inhibit the pathway that is used in dolichol synthesis, whereas Finasteride inhibits the enzyme that produces dolichol. Either way, it seems you’re looking down the barrel of the same gun when you mess with your dolichol.

I’ve considered another possibility involving the GPT gene’s expression. Because its expression can be spontaneously changed by the ER, and that it has both upper and lower limits of expression, if it’s overexpressed it can inhibit Lec35p and cause inefficient use of dolichol, however if it’s underexpressed it could cause a similar effect because it would be utilizing dolichol too slowly to keep up with your body’s demand for protein synthesis. Either outcome will result in dolichol deprivation, and it would correlate to why we don’t fully recover after we crash.

Another thing I’ve been thinking about was why PFS sufferers feel worse whenever they drink alcohol. The common conception has been that “alcohol lowers testosterone, therefore making us sick”. However people can drink themselves stupid and still come out without drastic hormone complications, why are we any different? Alcohol’s relation to dolichol could explain this:

Effect of alcohol on blood dolichol concentration.

Serum dolichol levels were studied in 95 active alcoholics and 16 abstinent alcoholics (at the time of blood sampling) and compared to those of 41 social drinkers. Active alcoholics had a significantly higher mean serum dolichol concentration (182.7 +/- 5.1 ng/ml, p less than 0.001 than either abstinent alcoholics (138.7 +/- 5.4 ng/ml) or social drinkers (142.1 +/- 4.1 ng/ml). During weekend (48 hr) heavy drinking (5.5 g of alcohol per kg b.w.) no significant changes were seen in mean serum dolichol concentrations in 10 healthy, nonalcoholic volunteers. Neither did moderate drinking for 10 days (60 g of alcohol daily)–preceded and followed by a period of abstinence–produce any significant changes in serum dolichol levels in 10 nonalcoholic subjects. During detoxification treatment of 12 alcoholics, mean serum dolichol concentration stayed constant for the first 7 days; on entering treatment it was 227.7 +/- 15.0 ng/ml, on the 3rd day 238.5 +/- 15.9 ng/ml, and on the 7th day of treatment 222.6 +/- 18.6 ng/ml. Our results show that as well as increasing urinary dolichol excretion, chronic alcohol abuse also produces increased serum dolichol concentrations. However, contrary to urinary dolichols, serum dolichol levels do not react significantly to heavy drinking lasting for 48 hr in nonalcoholic volunteers. Furthermore in alcoholics increased serum dolichol concentrations do not decrease as rapidly during abstinence as urinary dolichol concentrations do.

Drinking alcohol will cause you to excrete more dolichol, and losing dolichol will put stress on the endoplasmic reticulum. Your body appears to compensate with this by increasing production of dolichol, which will in turn attempt to restore balance. How does this relate to us? If we drink alcohol with an over/underexpressed GPT gene, then our already dolichol starved ER will become even more stressed, which would exacerbate our PFS symptoms.

I’ve been thinking a lot about the data collected so far. Most of our research and treatment up to this point has been based upon the premise that a dysfunctional endocrine system is the root cause of our symptoms. However, all of this data would suggest that our screwed up endocrine systems are merely a symptom themselves, and the root cause is actually an altered gene expression caused by stress of the endoplasmic reticulum caused by dolichol deprivation. This would also explain why TRT (among other treatments) usually only works temporarily, if at all. Replacing or attempting to balance our hormones will not fix the underlying issue, and would only serve as a symptomatic treatment. Our under-nourished bodies ewould not be able to sustain any prolonged hormonal adjustments, and would likely burn out under the stress and revert back to their weakened state.

With that said, I’d like to propose a proto-recovery protocol (it’s super-pro!). Assuming that dolichol deprivation was what caused our syndrome, and considering the fact that consuming alcohol depletes dolichol, which in turn will stress the ER (which exacerbates our symptoms), I would theorize that by increasing our dolichol (even to the point of overcompensating), it could potentially lessen the stress on the ER, which could possibly lead to the resolution of our entire syndrome. I would also theorize that if the stress on the ER that caused its UPR to cause a persistent underexpression/overexpression of the GPT gene, then perhaps lessening the stress on the ER could potentially convince it to cause a persistent normal expression of the GPT gene, which would make our recovery permanent (due to the fact that we do not have a defective SRD5A3 enzyme, therefore allowing for normal dolichol synthesis). Unfortunately dolichol supplements are currently not available, so we would have to seek an alternative source.

It sounds stupidly simple, but perhaps the cure for us is to eat a lot of raw uncooked spinach leaves. Spinach is one of the few natural sources of dolichol, and probably the only one that allows you to consume abnormally large amounts of it without making you sick. There’s no data available for how much spinach you would have to consume, or how much of its dolichol you would need, or even how long you would have to eat it for, so I’d simply recommend making at least one full meal a day consist almost entirely of raw uncooked spinach leaves, and continue to do so for at least a month. I’m sure most of us have eaten our share of raw spinach throughout our syndrome, but we probably haven’t eaten enough of it to make a substantial difference (or only had it as one of many ingredients, not as the primary focus). If we show any signs of improvement, we may have found the means to our cure.

I’m totally trying this. Any volunteers?

[mariobros]

Is it possible to have your dolichol levels tested?

[tryingnottoworry]

I do believe so, but I’m not sure if it would be the most accurate way to measure the condition. It would sort of be like if you got stabbed, and then a year later you tested for knives. While on fin, testing for dolichol would probably work well, as SRD5A3 is being inhibited, which directly causes dolichol deprivation. However post-fin test results would probably come back as dolichol being normal, as our SRD5A3 enzyme should be functioning normally, as fin has left our systems long ago and is no longer inhibiting it. The problem at that point probably wouldn’t be our “normal dolichol levels”, but our body’s efficiency of using the dolichol it has available through the up/downregulated GPT gene, or possibly even other genes that had their expressions altered.

However with that said, you bring up an excellent point: This dysfunctional process can definitely be revealed through proper testing. Testing for dolichol would probably be a good idea regardless, as even if it came back normal we would have a better understanding of how much of it our body needs. If it actually came back abnormally low (or even abnormally high), it could potentially point to an issue with SRD5A3. Testing for altered gene expressions, Lec35p efficiency (not just its levels), other CDG related tests, other dysfunctions along dolichol’s pathway, as well as dolichol itself would probably reveal a lot of much needed information. An expert on CDG testing would probably be the first place we should look, as they would probably have the best understanding of the mechanisms behind our condition.

[tryingnottoworry]

Wooooo! Great news!! It’s been about 2 days since I’ve started my raw uncooked spinach diet, and I’m getting massive improvements in all areas! I feel like I have energy again, my mind feels much more focused, my emotions and sense of humor are coming back, my libido increased, my genital numbness is wearing off, orgasm felt much better, ejaculate is slightly lighter in color and has a much creamier consistency, my penis feels warmer, my testicles stopped throbbing, erectile function has improved, and, oh man, I’m just feeling so much better. Even my weird prostate problem (the reason I took fin in the first place) that causes me to leak copious amounts of pre-ejaculate whenever I’m around or talking to my girlfriend has come back to how it was pre-fin. Every aspect of the syndrome seems to be wearing off at the same time, and I was up last night crying because I was so happy.

I’m almost taken aback by how quickly this has been reversing my symptoms. I’m one of the cases where fin crashed my system after only two days of use, so maybe my body is extra sensitive to dolichol deprivation? I have no idea. This treatment is unlike any other treatment we’ve tried before, except for maybe part of a raw food diet. I hope these improvements keep coming (and are sustained), because I’m feeling probably 99.9% right now.

I’m convinced more than ever that dolichol deprivation is what’s causing our suffering, and I implore all of you to try this. Raw uncooked spinach is safe, cheap, available everywhere, and is one of the few natural sources of dolichol (unless you want to eat a bunch of parsley instead). The kind I’ve been getting is organic baby spinach from Trader Joes (6oz per bag, 1 bag a day). It’s possible there may be some other variety of spinach that has a higher dolichol concentration, but we’d probably have to ask a botanist about that.

Anyway guys, until an actual dolichol supplement can be made available, this may be our best shot of having an effective treatment for PFS. Please give it a try.

[191]

This is amazing. When I read it I thought this is too good to be true. Fingers crossed.

I don’t normally pray mate but i’m praying you’re onto something!

Please give regular updates. Thanks mate.

19

[joetz]

@tryingnottoworry

Anyway guys, until an actual dolichol supplement can be made available, this may be our best shot of having an effective treatment for PFS. Please give it a try.

I’m waiting to see if you can stay in the zone. That’s the hardest thing about PFS, you think you are cured and out of the woods and the body forces itself into a state of misery again.

So one 6 oz bag of baby spinach every day? That’s a lot of spinach, lol
Hope you can manage that ok. Best of luck. I really hope you continue to feel better.

[kazman]

What do you intend to do about the amount of iron you’ll be absorbing from all the spinach you’re eating? Once iron levels significantly exceed 20% of your total iron binding capacity libido and erectile capability will drop.

Guess you could give blood every two weeks, but I think Red Cross limits you to once a month.

There is an alternate explanation as to why these raw food diets produce results for us, promise to start a thread on this soon.

Not trying to be critical, just trying to get you to think about all the various angles. - kazman

[tryingnottoworry]

Hey guys, thank you for your prayers and support, I really appreciate it! Things have been holding steady for day 3. My libido has been fluctuating slightly throughout the day between being decent and sub-par, though nothing drastic. It’s like a slightly weaker version of how my (pre-fin) body normally feels, but the fact that my libido is actually working in the first place is exhilarating. I actually FEEL like masturbating again, not just like I’m running a science experiment on myself (I’m sure you guys know what I mean). My penis is still a little bit numb, but it seems to be improving. My testicles have throbbed a few times since yesterday, but it was very breif and the pain was extremely light. All in all, good things are happening.

@kazman

What do you intend to do about the amount of iron you’ll be absorbing from all the spinach you’re eating? Once iron levels significantly exceed 20% of your total iron binding capacity libido and erectile capability will drop.

That’s a good question I hadn’t really considered. I did some research and it looks like I should be okay:

Is Spinach a good source of Iron?

Spinach - a source of Iron
Spinach is a source of non-heme iron, which is usually found in vegetable sources. Unlike heme iron found in animal products, non-heme iron is not as bioavailable to the body. According to the USDA National Nutrient Database, one cup of cooked spinach provides ~3.5mg of iron whereas a cup of raw spinach only contains 1 mg of iron.

Spinach - also inhibits iron absorption
Spinach also contains oxalic acid (sometimes referred as oxalate). Oxalic acid binds with iron, hence inhibiting its absorption.

Since I’m only eating raw spinach, it shouldn’t be as big of a problem. However I am eating way more than someone normally would, so I’ll just have to wait and find out (I’d still take too much iron over PFS any day). Also I just realized I haven’t explained why I’m advocating for raw spinach instead of cooked. Dolichol is similar to alcohol, and cooking foods with alcohol in them will remove the alcohol from them. I’m guessing dolichol would probably be removed much the same way.

Just to summarize, I made a simple chart about why it would seem that dolichol deprivation causes our syndrome to be persistent:

Hopefully by adding additional dolichol, it will convince the ER to bring the GPT’s expression down, thereby allowing for normal Lec35p function, and the resolution of PFS.

I’ve already found a connection for why alcohol exacerbates our symptoms, but caffeine has been reported to do the same in some people. How does it tie in with dolichol deprivation/stress on the ER?

Activation of Glycogen Phosphorylase with 5-Aminoimidazole-4-Carboxamide Riboside (AICAR)

This article links caffeine to interfering with part of the glycosylation process, which would explain why caffeine can have an adverse effect on some of us. It also has a lot of other great information (though quite complicated if you aren’t familiar with cellular biology).

I’ve been thinking about why spstriken has had such horrible side effects due to saw palmetto, even though it’s supposed to be much weaker than finasteride. Saw palmetto is essentially “weak dutasteride” in that it inhibits both 5 alpha reductase type 1 and 2, whereas fin mostly inhibits type 2. However in terms of 5 alpha reductase type 3, finasteride inhibits it about the same as type 2, but dutasteride inhibits it 50 times stronger.

Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride

To determine the effect of these inhibitors on SRD5a-3 activity, we compared their inhibitory effects using HEK-293 cells stably transfected with SRD5a-1, 2 and 3 expressing vectors. As illustrated in Figure 2 and Table 2, finasteride inhibits SRD5a-3 with similar potency SRD5a-3 (IC50s17.4 nM) and SRD5a-2 (IC50s14.3 nM). By contrast, dutasteride is approximately 50 times more potent to inhibit SRD5a-3 (IC50s0.33 nM) than finasteride (IC50s17.4"1.4 nM).

So if the mechanism of dutasteride and saw palmetto are the same, then that would suggest that saw palmetto has an extremely high effect on SRD5A3, possibly even higher than finasteride. This could definitely lead to severe dolichol deprivation.

It’s a little grueling to eat so much spinach every day, but adding a little variety can make it a bit more tolerable. I’ve been trying new salad dressings, stuffing sandwiches full of it, eating leaves like potato chips while watching TV, etc. You can add it to most foods without it affecting their flavor too much (just don’t cook it). Raw spinach can be a little bland, but I’m just glad we don’t have to eat jalapenos or persimmons or some other really harsh food. I’m very interested in seeing what effect the raw uncooked spinach diet has on the rest of us here, so please keep us updated if you’re giving it a try.

[boston332]

Thankfully, I really like Spinach and even prefer it raw to cooked. I’m going to grab a few bags today. I don’t really see how it could hurt.