α-Synuclein Is Degraded by Both Autophagy and the Proteasome*

By J. Webb, B. Ravikumar, J. Atkins, J. Skepper, D. Rubinsztein. Journal of Biological Chemistry, 2003

1,496 citations recorded by the source corpus.

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

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Neurology

View Paper: https://www.semanticscholar.org/paper/5cf927c33f8b82a1a3a7128fc3669f2334152064

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Citations in the corpus

Rapamycin alleviates toxicity of different aggregate-prone proteins. (2006, background): “We have previously shown that mutant huntingtin fragments, expanded polyalanines tagged to enhanced green fluorescent protein and forms of a-synuclein are autophagy substrates in cell models (13,14).”
Autophagy Is Activated for Cell Survival after Endoplasmic ReticulumStress (2006, background): “Both autophagy and ER stress have been implicated in certain human diseases, such as Parkinson’s disease ( 38 ) and Huntington’s disease (28, 30), and exploration of the novel signaling pathways relevant to ER stress and autophagy could lead to the development of new therapeutic strategies for these”
Lithium induces autophagy by inhibiting inositol monophosphatase (2005, methodology): “…clear the toxic, long-lived, aggregate-prone proteins, like mutant huntingtin and A53T, and A30P mutants of -synuclein (Ravikumar et al., 2002; Webb et al., 2003), which cause neurodegenerative disorders, such as Huntington’s disease (HD) (Rubinsztein, 2002) and forms of Parkinson’s disease…”
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. (2007, methodology): “Although these SMIRs and SMERs were discovered as modulators of the effects of rapamycin on yeast growth, we tested if they were also modulators of mammalian autophagy.”
α-Synuclein in Parkinson's disease. (2012, background): “It has been proposed that dysfunction of these degradation pathways may be a contributing factor to PD pathogenesis (Xilouri et al. 2008). a-Synuclein may also be turned over by the proteasome in other experimental settings (Tofaris et al. 2001; Webb et al. 2003).”