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The role of α-synuclein at the pre-synapse

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The presynaptic protein α-synuclein (aSyn) is an ‘intrinsically disordered protein’ which is highly dynamic in conformation. Transient intramolecular interactions between its charged N- and C-termini and between its hydrophobic region and the C-terminus prevent self-association. These interactions inhibit the formation of insoluble inclusions which are the pathological hallmark of Parkinson’s disease and many other synucleinopathies.

Furthermore, aSyn, is known to bind to small unilamellar vesicles (SUVs) via its N-terminus which forms an amphipathic alpha-helix upon membrane interaction. Here we show, that calcium binds to the C-terminus of alpha-synuclein, therewith increasing its lipid binding capacity. Using CEST -NMR we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N-terminus region, already known from studies on SUVs, and additionally via its C-terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synapse, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in-vitro.

Furthermore, aSyn aggregation spreads through the brain by the transfer of small fibrillary seeds, inducing the aggregation of normally folded endogenous alpha-synuclein once transferred to another cell. Here, we show that mitochondrial dysfunction directly aggravates preformed fibril (PFF)-induced alpha-synuclein seeding, while downstream effects of mitochondrial dysfunction, including inhibition of complex I, increase in cytosolic calcium or oxidative stress, were unable to induce the same effect. However, alpha-synuclein seeding was directly dependent on intramitochondrial proteostasis, as inhibition of the mitochondrial protease HtrA2, as well as inhibition of protein import into mitochondria increased alpha-synuclein seeding. This study extends the concept of mitochondria as guardian in cytosol (MAGIC) to the degradation of amyloidogenic proteins, including alpha-synuclein and β-amyloid 42 and draws a new picture of how mitochondria may affect neurodegenerative diseases.

This talk is part of the Biophysical Seminars series.

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