Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons

摘要: Fibrillar αSynuclein is the major constituent of Lewy bodies and neurites, protein deposits characteristic for Parkinson’s disease (PD). Multiplications gene, as well point mutations cause familial PD. However, exact role in neurodegeneration remains uncertain. Recent research invertebrates has suggested that oligomeric rather than fibrillizing mediates neurotoxicity. To investigate impact aggregation on progression neurodegeneration, we expressed variants with different fibrillation propensities rat substantia nigra (SN) by means recombinant adeno-associated viral (AAV) vectors. The formation proteinase K-resistant aggregates was correlated to loss nigral dopaminergic (DA) neurons striatal fibers. Expression two prefibrillar, structure-based design mutants (i.e., A56P A30P/A56P/A76P) resulted less aggregate DA compared human wild-type (WT) or inherited A30P mutation. only capable forming fibrils (WT/A30P), but not species induced a sustained progressive adult neurons. These results demonstrate divergent modes neurotoxicity exist invertebrate mammalian vivo suggest promotes degeneration found PD patients.