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

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