Alpha-Synuclein is degraded by both autophagy and the proteasome - PubMed (original) (raw)

. 2003 Jul 4;278(27):25009-13.

doi: 10.1074/jbc.M300227200. Epub 2003 Apr 28.

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• PMID: 12719433
• DOI: 10.1074/jbc.M300227200

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Alpha-Synuclein is degraded by both autophagy and the proteasome

Julie L Webb et al. J Biol Chem. 2003.

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Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. alpha-Synuclein is the major protein in Lewy bodies and rare mutations in alpha-synuclein cause early-onset PD. Consequently, alpha-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of alpha-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T alpha-synuclein can be switched on and off. We have used a panel of inhibitors/stimulators of autophagy and proteasome function and followed alpha-synuclein degradation in these cells. We found that not only is alpha-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of alpha-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of alpha-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

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