Alpha Synuclein: New Species is discovered called Pa-syn - could it be the cause of cell death in PD?

[p-oui]

OK, Here's my (simplistic) take away:

1. PD is caused by lack of dopamine. In PD brain autopsies, we often see Lewy bodies.

2. Lewy bodies are at least largely made up of protein, but a misfolded protein, called alpha synuclein (ASN). Because it is misfolded, it does not transfer signals between neurons properly.

3. Removing the ASN clumps *might* help halt the progression of PD, hence the clinical trials emerging, like PASADENA.

Some questions around Lewy bodies were presented in the blog "Are Lewy bodies fake news?" scienceofparkinsons.com/201...

It discusses the idea that there are different types of ASN and cites other findings that support this, "dopamine cells may be dying before Lewy bodies even have a chance to form, which would suggest that the presence of Lewy bodies does not predispose a neuron to cell death." Begging the question: Are these ASN clumps the cause of PD or a response to cell death in PD? So, If ASN clumping is not causing neuron death (which causes loss of dopamine which causes PD) then what does?

Then, "Alpha Synuclein: New Species" was just posted:

scienceofparkinsons.com/201...

It includes the announcement that two Florida researchers had identified an all new species of alpha synuclein that they have called “P-alpha-syn-star” or Pα-syn* (that I posted a few days ago). Pa-syn appears to be a mini clump of protein inside the larger alpha synuclein clump inside the lewy body (again my simplistic understanding) and these Pa-syn are like toxic missiles seeking mitochondria then destroying them. Could this be the real culprit behind PD?

This seems to open an important door and stir a lot of additional questions. I am excited to hear more. What do you think?

More info: pnas.org/content/early/2018...

[park_bear]

"We showed that pα-syn* is made of trimmed α-synuclein resulting from a failed cellular attempt to degrade fibrillar α-synuclein aggregates. "

Good work - another piece of the puzzle put into place.

[p-oui in reply to park_bear]

I think so - I am hopeful about this

[Dee1980]

Good stuff.

So many questions still, such as why these proteins misfold, why aren't the chaperones and the proteasome (if I have that right) doing their job? Everyone has ASN, everyone has errors in folding proteins, why is it prevalent in Parkinsons? What makes PWP different?

Another piece in this puzzle:

hindawi.com/journals/omcl/2...

"Lewy bodies are intracellular inclusions formed mainly by alpha-synuclein, a protein of unknown function that is present close to synaptic terminals; the oligomerization of this protein is considered a key event in the setup or development of the disease [31]. One of the reported copper-damaging mechanisms is the oligomerization of alpha-synuclein [32]; in fact, it is claimed by some authors that copper is highly efficient in producing the oligomerization of alpha-synuclein [33] and that this metal, and not iron, is selectively able to fibrillate alpha-synuclein [34]. That was also related to the ability of copper to cause oxidative damage because the alpha-synuclein oligomerization is linked to damage to the mitochondria and electron chain transfer."

[Ajssister]

Really interesting. Thx for posting.