α-synuclein degradation by autophagic pathways: A potential key to Parkinson's disease pathogenesis

Abstract

The neuronal protein α-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Excessive wild type α-synuclein levels can lead to PD in select familial cases and α-synuclein protein accumulation occurs in sporadic PD. Therefore, elucidation of the mechanisms that control α-synuclein levels is critical for PD pathogenesis and potential therapeutics. The subject of α-synuclein degradation has been controversial. Previous work shows that, in an assay with isolated liver lysosomes, purified wild type α-synuclein is degraded by the process of chaperone-mediated autophagy (CMA). Whether this actually occurs in a cellular context has been unclear. In our most recent work, we find that wild type α-synuclein, but not the closely related protein β-synuclein, is indeed degraded by CMA in neuronal cells, including primary postnatal ventral midbrain neurons. Macroautophagy, but not the proteasome, also contributes to α-synuclein degradation. Therefore, two separate lysosomal pathways, CMA and macroautophagy, degrade wild type α-synuclein in neuronal cells. It is hypothesized that impairment of either of these two pathways, or of more general lysosomal function, may be an initiating factor in α-synuclein accumulation and sporadic PD pathogenesis. ©2008 Landes Bioscience.