alpha-synuclein degradation by autophagic pathways: a potential key to Parkinson's disease pathogenesis.
The neuronal protein alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Excessive wild type alpha-synuclein levels can lead to PD in select familial cases and alpha-synuclein protein accumulation occurs in sporadic PD. Therefore, elucidation of the mechanisms that control alpha-synuclein levels is critical for PD pathogenesis and potential therapeutics. The subject of alpha-synuclein degradation has been controversial. Previous work shows that, in an assay with isolated liver lysosomes, purified wild type alpha-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 alpha-synuclein, but not the closely related protein beta-synuclein, is indeed degraded by CMA in neuronal cells, including primary postnatal ventral midbrain neurons. Macroautophagy, but not the proteasome, also contributes to alpha-synuclein degradation. Therefore, two separate lysosomal pathways, CMA and macroautophagy, degrade wild type alpha-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 alpha-synuclein accumulation and sporadic PD pathogenesis.
Xilouri
Maria
M
Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Vogiatzi
Tereza
T
Vekrellis
Kostas
K
Stefanis
Leonidas
L
D000818:Animals; D001343:Autophagy; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism*
D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; D051844:alpha-Synuclein