Glutathione depletion and overproduction both initiate degeneration of nigral dopamin
 

Acta Neuropathol. 2010 Dec 30. [Epub ahead of print]
Glutathione depletion and overproduction both initiate degeneration of nigral dopaminergic neurons.
Garrido M, Tereshchenko Y, Zhevtsova Z, Taschenberger G, Bähr M, Kügler S.

Department of Neurology, Center of Molecular Physiology of the Brain (CMPB) at University Medicine Göttingen, Waldweg 33, 37073, Göttingen, Germany.
Abstract
Parkinson's disease is a neurodegenerative disorder characterized by severe motor deficits mainly due to degeneration of dopaminergic neurons in the substantia nigra. Decreased levels of the cell's most important anti-oxidant, glutathione, have been detected in nigral neurons of Parkinson patients, but it is unknown if they are the cause or merely the consequence of the disease. To elucidate if glutathione depletion causes selective degeneration of nigral dopaminergic neurons, we down-regulated glutathione synthesis in different brain areas of adult rats by a viral vector-based RNAi approach. Decreased glutathione synthesis resulted in progressive degeneration of nigral dopaminergic neurons, while extra-nigral and striatal neurons were significantly less vulnerable. Degeneration of dopaminergic neurons was accompanied by progressive protein aggregate formation and functional motor deficits and was partially rescued by α-synuclein. That the survival of nigral dopaminergic neurons depends on the precise control of glutathione levels was further demonstrated by significant degeneration induced through moderate overproduction of glutathione. Over-expression of either of the two subunits of glutamate-cysteine ligase induced aberrant glutathiolation of cellular proteins and significant degeneration of dopaminergic neurons. Thus, while glutathione depletion was demonstrated to be a selective trigger for dopaminergic neuron degeneration, a glutathione replacement approach as a potential treatment option for Parkinson's patients must be considered with great care. In conclusion, our data demonstrate that survival of nigral dopaminergic neurons crucially depends on a tight regulation of their glutathione levels and that the depleted glutathione content detected in the brains of Parkinson's disease patients can be a causative insult for neuronal degeneration.

PMID: 21191602 [PubMed - as supplied by publisher]

thanks madelyn
 

i completely forgot how to spell your name. thanks for posting this. glutathione is something i know little about but it sounds like it is a player in the pd mystery, perhaps a big player. The major antioxidant in our bodies.

wikipedia says among many other things about glutathione:

is essential for the immune system to exert its full potential, e.g., (1) modulating antigen presentation to lymphocytes, thereby influencing cytokine production and type of response (cellular or humoral) that develops, (2) enhancing proliferation of lymphocytes, thereby increasing magnitude of response, (3) enhancing killing activity of cytotoxic T cells and NK cells, and (4) regulating apoptosis, thereby maintaining control of the immune response.[citation needed]

It plays a fundamental role in numerous metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs.[4]

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

An eye opener !
 

Thank you Madelyn for sharing the paper. I am struck by the following:
" That the survival of nigral dopaminergic neurons depends on the precise control of glutathione levels was further demonstrated by significant degeneration induced through moderate overproduction of glutathione. Over-expression of either of the two subunits of glutamate-cysteine ligase induced aberrant glutathiolation of cellular proteins and significant degeneration of dopaminergic neurons"
It is a delicate balance. Too much glutathion is just as bad as too little and only God knows the right balance.
I take a lot of antioxidants and now I am wondering if it is doing me good or bad !? :confused:
Imad

Does this mean what I read it to mean?
 

".....Degeneration of dopaminergic neurons was accompanied by progressive protein aggregate formation and functional motor deficits AND WAS PARTIALLY RESCUED BY A-SYNUCLEIN...."

This sounds to me like a-synuclein is protective rather than causative...in which case therapies, including Affiris' PD vaccine they are working on (which I understand keeps a-synuclein plaques from forming and/or busts them up?) would make things worse, not better? Tell me it isn't so.

don't know
 

I'm hoping they know something we do not because I can't understand how they can block something when they don't know it's function in the first place.

This should clear things up
 

Madelyn,

Please see the following link to the MJFF position paper on alpha-synuclein



I'd add that the MJFF paper is a bit out of date. See the updated MJFF a-synuclein summit results at PD Online Research.

I think it is pretty well established that we all have this protein in our brain and that in its normal state it is helpful. Researchers have found that the protein gathers in clumps or aggregates in the PD brain. This replication of proteins "gone bad" is a causative or result of PD; they do not know, but either way it results in the continued loss of our cells, so blocking them would theoretically halt the disease.

As for the vaccine itself, I think it holds a lot of promise and maybe to further substantiate that is the main culprit in our case, is that a major pharma here purchased exclusive rights to develop immune therapy involving a-synuclein to the sum of $427 million. That is a lot of money to throw away on something if they are not certain this is a major factor. Further, MJFFF is funding the vaccine research at U of Nebraska, and I don't think they would touch it if they thought it harmful. My concern with a vaccine is that they somehow can trigger disease onset in some people who have a genetic aberration that makes their brain more sensitive to inflammation and/our causes a faulty auto immune reaction.

Hope this helps!

Laura

iv glutathione
 

The abstract was disconcerting to me,also. May explain the negative results from the placebo controlled study conducted in florida testing dr. david perlmutter's protocol of IV glutathione.(hauser, et al, 2009).
though it was a very small study lasting a very short period of time.

Northwest Parkinson's foundation reported upon the results of the 2 studies using IV glutathione

http://www.nwpf.org/wellness/Physica...97&headerbar=4

[two studies reported in this article] thus far ask the question, “Does glutathione improve symptoms in PD?”... a topic of debate in the medical community, because no one has been able to propose a mechanism by which glutathione might offer symptomatic relief. Continued interest in glutathione explores this molecules anti-oxidant properties. The loss of glutathione in the substantia nigra precedes PD symptoms by more than a decade, and occurs prior to the formation of Lewy bodies, considered a PD precursor. Just because low glutathione levels correlate with PD severity, doesn’t mean that the loss of glutathione causes the disease. This is highlighted by the fact that glutathione is decreased in many diseases including cancer, vascular disease and other diseases of aging. We have no idea whether glutathione has the potential to retard disease progression, as the study has not yet been done..."

old age gene
 

it appears, even tho i can clearly recall Joan Samuelson, who was merely reflecting on the belief at the time [over a decade ago] that pd was not premature aging, that it is exactly it. so many things that occur normally with aging are happening to us. is there an old age gene or aging gene? and it's got to have a toxic trigger. Laura you are right, a vaccine does provide hope for the future.

bumping up
 

recent post about glutathione prompted searching this previous discussion. madelyn

I feel none the wiser for looking through everything in this post. There is too much that is contradictory. The only thing that seems to make sense is that this is another thing where it seems that imbalance is causative.

Thinking of the maps that show prevalence..... and imbalance. Where do these things connect...

Brain chemistry is such a difficult thing to comprehend, it is not static for one thing. So when you look at something in a petri dish or under a microscope or a bunch of statistics you are looking for something fixed, provable. Cause and effect.

But all the neurotransmitters are dancing - except when they don't work, or disappear - I am starting to think that they really need to use all that fancy neuro-imaging stuff much more creatively - not just for diagnostics, but to look at the dance...... and how the brain regulates the dance......