, Volume 57, Issue 13-14, pp 1894-1908

Alpha-synuclein and Parkinson's disease

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Abstract.

The involvement of α-synuclein in neurodegenerative diseases was first suspected after the isolation of an α-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD). Later, two different α-synuclein mutations were shown to be associated with autosomal-dominant Parkinson's disease (PD), but only in a small number of families. However, the discovery that α-synuclein is a major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD, confirmed its role in PD pathogenesis. Pathological aggregation of the protein might be responsible for neurodegeneration. In addition, soluble oligomers of α-synuclein might be even more toxic than the insoluble fibrils found in Lewy bodies. Multiple factors have been shown to accelerate α-synuclein aggregation in vitro. Therapeutic strategies aimed to prevent this aggregation are therefore envisaged. Although little has been learned about its normal function, α-synuclein appears to interact with a variety of proteins and membrane phospholipids, and may therefore participate in a number of signaling pathways. In particular, it may play a role in regulating cell differentiation, synaptic plasticity, cell survival, and dopaminergic neurotransmission. Thus, pathological mechanisms based on disrupted normal function are also possible.

Received 3 May 2000; revised 3 July 2000; accepted 3 July 2000