Parkinson's Disease as Localized Garbage Catastrophe
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Alpha-synuclein is associated with Parkinson's disease (PD), and is believed to play a central role in the mechanisms that cause the destruction of dopamine-generating neurons, and thus the pathology of the condition. Here, researchers dig deeper into the processes involved:

Overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells' center, with the potential consequence of progressive degeneration and eventual cell death. "This is an important new insight. I don't think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD."

Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy, [the] scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein. They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal - part of the junction where axons and dendrites of brain cells meet to exchange chemical signals.

"The over-expression of alpha-synuclein caused hypertrophy in these terminals. The terminals were enlarged, filled with structures we normally don't see." [As] alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die.

Link: http://www.sciencedaily.com/releases/2013/02/130207141402.htm

Comments

I wonder if it might be feasible to mark intracellular junk (alpha-synuclein in this case, but also hyperphosphorylated tau and such) for excretion by the cell. Sure, it's trading one problem for another since you'd be creating extracellular junk, but it's hard to imagine that any place could be worse for the junk to be than inside the very delicate neuronal projections. Perhaps the choroid plexus system would then clear it from CSF or the immune system would pick it up.

Posted by: José at February 8, 2013 10:22 AM

Perhaps some of the approaches in the following papers may be effective:
"Mechanisms of α-Synuclein Aggregation and Toxicity"
(D-ß-hydroxybutyrate, TUDCA, probucol)
http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA467589

"Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds"
http://www.sciencedirect.com/science/article/pii/S0014579311002122

"Effects of Various Flavonoids on the α-Synuclein Fibrillation Process"
http://www.hindawi.com/journals/pd/2010/650794/

"Curcumin Prevents Aggregation in -Synuclein by Increasing Reconfiguration Rate"
http://www.jbc.org/content/287/12/9193.short

"Black Tea Theaflavins Inhibit Formation of Toxic Amyloid-β and α-Synuclein Fibrils"
http://pubs.acs.org/doi/abs/10.1021/bi2012383

Posted by: Lou Pagnucco at February 8, 2013 4:44 PM
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