Abstract
Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson’s disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-015-0230-9) contains supplementary material, which is available to authorized users.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting over 2% of the population over 65 years of age
We found that p62 levels were reduced in STR, substantia nigra (SN) and HIP regions in response to hypoxia in wild-type mice, similar to the known mitochondrial substrates of parkin, while its protein levels were maintained in other brain regions and in
We found that the degradation of p62 can be blocked by the proteasomal inhibitor-MG132 even in Atg5−/− MEF cells (Fig. 3)
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting over 2% of the population over 65 years of age. Sporadic PD or “classical parkinsonism” accounts for the majority of the disease and is multisystem neurodegenerative disorders, morphologically characterized. The formation of LBs includes the stepwise condensation to ubiquitinated dense filamentous inclusions with incorporation of alpha-synuclein (Singleton et al, 2003; Spillantini et al, 1997) or p62 (Nakaso et al, 2004), which invoke the death and disappearance of the involved neurons, and ubiquitination seems to increase aggregation and neurotoxicity of alphasynuclein in cultured human dopaminergic cells (Lee et al, 2008; Rott et al, 2008). Mutations in parkin represent one of the major causes of early-onset familial PD (Biskup et al, 2008; Kitada et al, 1998; Lesage and Brice, 2009); It was proposed that mutations in parkin, an E3 ubiquitin ligase which ubiquitinates and degrades a diverse array of substrates, would cause accumulation and aggregation of these substrates due to
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