Alpha-Synuclein is degraded by both autophagy and the proteasome.
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.
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/Medical Research Council Building, Addenbrooke's Hospital, Hills Road, United Kingdom.
Julie L
JL
Webb
Brinda
B
Ravikumar
Jane
J
Atkins
Jeremy N
JN
Skepper
David C
DC
Rubinsztein
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D051843:Synucleins; D051844:alpha-Synuclein
D000903:Antibiotics, Antineoplastic; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus