yes i do remember that Carey because it was his first time he presented it outside of a medical audience and he broke the news to us about pd not being just a motor disorder and talked about braak and pre-pd symptoms, very enlightening and validated much of what we were experiencing. He didn't know what to expect but it went fine.

This post may be too long to read!
Here is my take on alpha-syn-centric view of PD! A better version of it would be in our book (hope so!).........


Report #1 Alpha-Synuclein and PD (Bhatt et al) ;
Alpha-synuclein1,2 is a 140-amino-acid-long protein expressed in dopaminergic neurons. It’s a membrane bound alpha-helical chaperone protein. It contains a unique amyloidogenic domain within its midregion that dimerizes readily to form fibrillar structures in vitro which closely resemble those in pathogenic Lewy bodies3 (Fig. 1). Point mutations (A30P, A53T, and E46K) in alpha-syn have been found to be pathogenic for familial4,5 forms of PD, and alpha-syn is the major component of Lewy bodies5 and Lewy neurites in the brain biopsies of sporadic PD patients. Both the mutations at A53T and E46K accelerate fibril formation in-vitro assays, suggesting that accelerated polymerization of alpha-syn may be responsible for PD in patients harboring these mutations.5,6 Other factors, such as truncation by proteases, metals and oxidative/nitrative challenge, also accelerate fibril formation5-Transgenic mice expressing a truncated form of alpha-syn that fibrillizes more readily than the full-length protein in vitro showed evidence of substantia nigra Lewy bodies and neurodegeneration.

Report #2: α-synuclein inhibits autophagy (Winslow A, Rubinsztein DC 2011).
Parkinson disease (PD) is ………… α-synuclein
accumulation is toxic. Here we review our recent study showing that α-synuclein
inhibits autophagy. We discuss our mechanistic understanding of this phenomenon
and also speculate how a deficiency in autophagy may contribute to a range of
pleiotropic features of PD biology.

Report #3 Zelda H Cheung1 and Nancy Y Ip 1 2009
Various pathogenic mechanisms have been associated with neuronal loss in PD, including oxidative stress, mitochondrial dysfunction, protein aggregation and abnormality with the ubiquitin-proteasome pathway [3]. In particular, identification of autosomal dominant and autosomal recessive mutations in cases of familial PD has significantly contributed to our current understanding of the pathogenesis of PD. For example, autosomal dominant A53T and A30P mutation of alpha-synuclein, the main constituent of Lewy bodies, is associated with familial PD [4,5]….to a pivotal involvement of alpha-synuclein and protein aggregation in the pathogenesis of PD. Presence of protein aggregates in PD brains could also be attributed to deregulation of the ubiquitin-proteasome degradation system. Mutations in Parkin, an ubiquitin E3-ligase, and ubiquitin-C-terminal hydrolase-L1 (UCH-L1), a protein that is involved in the degradation of poly-ubiquitin chains, are both associated with familial PD cases [9,10]. On the other hand, evidence in support of a role of mitochondrial dysfunction in PD came from the identification of mutations in PINK1 and Parkin, both of which have been demonstrated to regulate mitochondrial morphology and function [11,12].
Interestingly, recent studies reveal that deregulation of autophagy is evident in the brains of PD patients [3].
Autophagy is traditionally considered as a cellular homeostatic process pivotal for bulk degradation of cytoplasmic contents and organelles. The autophagic pathway is responsible for the degradation of long-lived proteins, protein aggregates and cytoplasmic organelles [14]
Report #4
Modified forms of alpha syn, (nitrated, as well as aggregated forms) activate microglia and induce proinflammatory cytokine production and the infiltration of immune cells (including CD4 T cells) into the brain, contributes to neuroinflammation.

Based on these papers, here is my simplified version

Problem #1: Genetic aberrations and/or environmental triggers induce aggregation of alpha-syn, interrupt its ability to chaparone function.
Problem #2: Aggregated alpha-syn is toxic to neuronal cells
#3: Aggregated alpha-syn released from the dying neurons activate microglia in the brain, proinflammatory cytokines are produced leading to neuroinflammation.
#4: Aggregated alpha-syn inhibits autophagy, so cells fail to recycle their “bad proteins” as well as aged mitochondria.
#5. Old mitochondria fail to function, oxidative stress, insufficient/no ATP production. Neuronal functions requiring energy fail
#6. Mutations in genes like Parkin etc., that are involved in Ubiquitin-mediated protein degradation enhance neuronal death

In addition, this is what I propose:
Problem #7: Aggregated alpha-syn leaks out of the brain, gets into blood and enters peripheral organs. Immune system perceives this modified version as a pathogen or a “danger” signal and generates T cells reactive to aggregated alpha-syn. These T cells seek out cells “infected” with modified alpha-syn, i.e., neurons and effectively kill or silence them.

Problem #8: Compromised BBB due to inflammation might enhance T cell entry to the brain

Problem #9: If there is an infection, viral/bacterial might produce proteins that are similar to aggregared form of alpha-syn (its called molecular mimicry) peptides and the immune system generates T cells and antibodies that are capable of attacking cells that are infected with the pathogen as well as cells expressing alpha0syn i.,e neurons/
Even after the pathogen clearance, T cells remain active because they react to alpha-syn floating in the body and remain active till the “infection” is cleared.
Problem #10. Increased state of inflammation due to real infections or perceived infections
enhances neuronal death and/or silencing.

1. Acta Neuropathol. 2008 Apr;115(4):479-89. Epub 2008 Jan 10.

Curcumin inhibits aggregation of alpha-synuclein.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE.

Department of Anatomy and Neurobiology, Washington University School of Medicine,
St Louis, MO 63110, USA.

Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in
Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is
structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid
and prevent further oligomerization of Abeta monomers onto growing amyloid
beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid
formation are similar in Parkinson's disease (PD) and AD, we investigated the
effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of
AS aggregation was developed by treatment of purified AS protein (wild-type) with
1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin
inhibited aggregation in a dose-dependent manner and increased AS solubility. The
aggregation-inhibiting effect of curcumin was next investigated in cell culture
utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in
which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and
its aggregation examined under different concentrations of curcumin. To estimate
aggregation in an unbiased manner, a protocol was developed in which the images
were captured automatically through a high-throughput cell-based screening
microscope. The obtained images were processed automatically for aggregates
within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant
alpha-synuclein aggregation was observed within 48 h subsequent to curcumin
addition. Our data suggest that curcumin inhibits AS oligomerization into higher
molecular weight aggregates and therefore should be further explored as a
potential therapeutic compound for PD and related disorders.


PMID: 18189141 [PubMed - indexed for MEDLINE]


1. J Biol Chem. 2004 Jun 25;279(26):26846-57. Epub 2004 Apr 19.

The flavonoid baicalein inhibits fibrillation of alpha-synuclein and
disaggregates existing fibrils.

Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL.

Department of Chemistry and Biochemistry, University of California, Santa Cruz,
California 95064, USA.

The aggregation of alpha-synuclein has been implicated as a critical step in the
development of Parkinson's disease. Parkinson's disease is a progressive
neurodegenerative disorder caused by the loss of dopaminergic neurons from the
substantia nigra; currently, no cure exists. Baicalein is a flavonoid with
antioxidant properties; upon oxidation, it forms several products including
quinones. We show here that low micromolar concentrations of baicalein, and
especially its oxidized forms, inhibit the formation of alpha-synuclein fibrils.
In addition, existing fibrils of alpha-synuclein are disaggregated by baicalein.
The product of the inhibition reaction is predominantly a soluble oligomer of
alpha-synuclein, in which the protein molecules have been covalently modified by
baicalein quinone to form a Schiff base with a lysine side chain in
alpha-synuclein. The binding of baicalein was abolished by conversion of the Tyr
residues into Phe, demonstrating that Tyr is involved in the interaction of
alpha-synuclein with baicalein. In disaggregation baicalein causes fragmentation
throughout the length of the fibril. These observations suggest that baicalein
and similar compounds may have potential as therapeutic leads in combating
Parkinson's disease and that diets rich in flavonoids may be effective in
preventing the disorder.


PMID: 15096521 [PubMed - indexed for MEDLINE]


1. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. Epub 2010 Apr 12.

EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces
cellular toxicity.

Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker
EE.

Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125
Berlin-Buch, Germany. jbiesch@mdc-berlin.de

Protein misfolding and formation of beta-sheet-rich amyloid fibrils or aggregates
is related to cellular toxicity and decay in various human disorders including
Alzheimer's and Parkinson's disease. Recently, we demonstrated that the
polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and
amyloid-beta fibrillogenesis. It associates with natively unfolded polypeptides
and promotes the self-assembly of unstructured oligomers of a new type. Whether
EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we
show that EGCG has the ability to convert large, mature alpha-synuclein and
amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic
to mammalian cells. Mechanistic studies revealed that the compound directly binds
to beta-sheet-rich aggregates and mediates the conformational change without
their disassembly into monomers or small diffusible oligomers. These findings
suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.


PMCID: PMC2867908
PMID: 20385841 [PubMed - indexed for MEDLINE]

Good timing; I just ran across an abstract in Acta Neurologica (120:1)


Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson’s disease, neuronal α-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time.

Girija, can you see a viral or bacterial infection that is never fully eradicated as a trigger event or the "main" event that causes the vicious folded a-synuclein inflammatory circle.

Your hypothesis correlates to research finding on H. pylori, the intestinal infection, that causes ulcers. In people with PD who also have a pylori bacterial infection, eradicating the virus led to symptom improvement in all cases and in some what would appear a reversal of disease.

Laura

Okay, so I start up the curcumin regimen in earnest today and stick with it. This certainly explains Ron Hutton's turnaround.

What I can't figure out is if PD is prion based, why is it expressed so differently. We all share a lengthy pre-symptomatic period, but the known prion diseases result in rapid decline and early death. We have slow decline and no so called direct fatality. In fact, in YOPD, we take a big hit and then sort of stabilize into slow decline. Plus, in prion disease there is a noted absence of inflammation! I am guessing our immune system is protecting from us from a much more grim prognosis.

Just wondering? Any ideas?

Laura

Laura, I thought the article said that it behaved in a prion like fashion, not that it was a prion....... or did I misunderstand.....

Lindy

Actually before BSE there was Kuru, which took a long time to develop.....

Lindy,

No you are correct; the article I cited did not come out and declare it as such, but Paula's article from 2009, pretty much did. I was accepting of both or one rather substantiating the other. I think scientists had suggested this idea before

The definition of prion itself fits what researchers describe happening in PD:

Prion: A disease-causing agent that is neither bacterial nor fungal nor viral and contains no genetic material. A prion is a protein that occurs normally in a harmless form. By folding into an aberrant shape, the normal prion turns into a rogue agent. It then co-opts other normal prions to become rogue prions.

From what I have been reading, it seems that the aberrant proteins alone do not make it a prion disease, the missing link was the infectious part- this is what set PD and AZ apart from prion based encephalopathies. By showing the proteins are infectious, it moves it one step closer to true prion disorder.

Even the researcher who won Nobel Prize for discovery of prions seems to be swayed. Olanaw, a name we all probably recognize, and Prusiner the Nobel recipient recenty co-authored the article full-text here.
They make a pretty convincing argument.

The prion disorders kill off neurons all over the brain and rather quickly, but there is no auto immune response; we just take a localized hit but have chronic inflammation. Also, we leave behind protein tangles in form of Lewey Bodies while classic prion disorders leave damaged tissue full of holes. Maybe there turns out to be a spectrum of prion disorders?

One interesting thing I ran across is that it is believed alpha-syn manages transport and levels of copper, so I think of Wilson's Disease and how it mimics PD through inability to process copper out of brain...wonder if the copper is important somehow in our disease pathology?
Laoa

They've been discussing this for awhile but now, as Langston said in one article, many things are coming together about Parkinson disease.

this is a page of links all concerning pd being prion disease.

laura i like your definition and am writing about this as we speak for the book. can you give me a source for that? I would like to use it. never mind found it!
thanks!

http://www.pdonlineresearch.org/sear...rion%20disease

Here are names that many of you will recognize commenting on this. it's the same link as in my first post in this thread but these are medical thought leaders - Olanow, Lang, Langston and more.

excerpt:

ARTICLE IN BRIEF

A theory gaining traction among some Parkinson disease (PD) experts is that PD may be a prion-like disorder, based on evidence that alpha-synuclein can be transmitted from neuron to neuron, leading to the development of Lewy body-like inclusions in the receiving cell, and other findings from neuroanatomy, fetal transplantation surgery, and basic science.
Is Parkinson disease (PD) a prion-like disorder, with alpha-synuclein playing the role of infectious protein? The answer to that provocative question may be “yes,” according to a growing number of PD experts, as they consider findings from neuroanatomy, fetal transplantation surgery, and basic science


http://journals.lww.com/neurotodayon...xperts.12.aspx