Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death.
Expansion of the polyQ repeat in ataxin-2 results in degeneration of Purkinje neurons and other neuronal groups including the substantia nigra in patients with spinocerebellar ataxia type 2 (SCA2). In animal and cell models, overexpression of mutant ataxin-2 induces cell dysfunction and death, but little is known about steady-state levels of normal and mutant ataxin-2 and cellular mechanisms regulating their abundance. Based on preliminary findings that ataxin-2 interacted with parkin, an E3 ubiquitin ligase mutated in an autosomal recessive form of Parkinsonism, we sought to determine whether parkin played a role in regulating the steady-state levels of ataxin-2. Parkin interacted with the N-terminal half of normal and mutant ataxin-2, and ubiquitinated the full-length form of both wild-type and mutant ataxin-2. Parkin also regulated the steady-state levels of endogenous ataxin-2 in PC12 cells with regulatable parkin expression. Parkin reduced abnormalities in Golgi morphology induced by mutant ataxin-2 and decreased ataxin-2 induced cytotoxicity. In brains of SCA2 patients, parkin labeled cytoplasmic ataxin-2 aggregates in Purkinje neurons. These studies suggest a role for parkin in regulating the intracellular levels of both wild-type and mutant ataxin-2, and in rescuing cells from ataxin-2-induced cytotoxicity. The role of parkin variants in modifying the SCA2 phenotype and its use as a therapeutic target should be further investigated.
Huynh
Duong P
DP
Rose Moss Laboratory for Parkinson and Neurodegenerative Diseases, Burns and Allen Research Institute, and Division of Neurology, Cedars-Sinai Medical Center, USA.
Nguyen
Dung T
DT
Pulst-Korenberg
Johannes B
JB
Brice
Alexis
A
Pulst
Stefan-M
SM
D000818:Animals; D000067528:Ataxins; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism; D014162:Transfection; D014343:Trypan Blue; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology
D000067528:Ataxins; D009419:Nerve Tissue Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D014343:Trypan Blue