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SUMMARY:The role of α-synuclein at the pre-synapse - Dr. Gabriele Kaminsk
 i Schierle\, Dept. of Chemical Engineering and Biotechnology\, University 
 of Cambridge
DTSTART:20181121T103000Z
DTEND:20181121T113000Z
UID:TALK114943@talks.cam.ac.uk
CONTACT:Ryan Limbocker
DESCRIPTION:The presynaptic protein α-synuclein (aSyn) is an ‘intrinsic
 ally disordered protein’ which is highly dynamic in conformation. Transi
 ent intramolecular interactions between its charged N- and C-termini and b
 etween its hydrophobic region and the C-terminus prevent self-association.
  These interactions inhibit the formation of insoluble inclusions which ar
 e the pathological hallmark of Parkinson’s disease and many other synucl
 einopathies.\n \nFurthermore\, aSyn\, is known to bind to small unilamella
 r vesicles (SUVs) via its N-terminus which forms an amphipathic alpha-heli
 x upon membrane interaction. Here we show\, that calcium binds to the C-te
 rminus of alpha-synuclein\, therewith increasing its lipid binding capacit
 y. Using CEST-NMR we reveal that alpha-synuclein interacts with isolated s
 ynaptic vesicles with two regions\, the N-terminus region\, already known 
 from studies on SUVs\, and additionally via its C-terminus\, which is regu
 lated by the binding of calcium. Indeed\, dSTORM on synaptosomes shows tha
 t calcium mediates the localization of alpha-synuclein at the pre-synapse\
 , and an imbalance in calcium or alpha-synuclein can cause synaptic vesicl
 e clustering\, as seen ex vivo and in-vitro. \n\nFurthermore\, aSyn aggreg
 ation spreads through the brain by the transfer of small fibrillary seeds\
 , inducing the aggregation of normally folded endogenous alpha-synuclein o
 nce transferred to another cell. Here\, we show that mitochondrial dysfunc
 tion directly aggravates preformed fibril (PFF)-induced alpha-synuclein se
 eding\, while downstream effects of mitochondrial dysfunction\, including 
 inhibition of complex I\, increase in cytosolic calcium or oxidative stres
 s\, were unable to induce the same effect. However\, alpha-synuclein seedi
 ng was directly dependent on intramitochondrial proteostasis\, as inhibiti
 on of the mitochondrial protease HtrA2\, as well as inhibition of protein 
 import into mitochondria increased alpha-synuclein seeding. This study ext
 ends the concept of mitochondria as guardian in cytosol (MAGIC) to the deg
 radation of amyloidogenic proteins\, including alpha-synuclein and β-amyl
 oid 42 and draws a new picture of how mitochondria may affect neurodegener
 ative diseases. \n
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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