| First Author | Usenovic M | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 12 | Pages | 4240-6 |
| PubMed ID | 22442086 | Mgi Jnum | J:183462 |
| Mgi Id | MGI:5318786 | Doi | 10.1523/JNEUROSCI.5575-11.2012 |
| Citation | Usenovic M, et al. (2012) Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. J Neurosci 32(12):4240-6 |
| abstractText | The autophagy-lysosomal pathway plays an important role in the clearance of long-lived proteins and dysfunctional organelles. Lysosomal dysfunction has been implicated in several neurodegenerative disorders including Parkinson's disease and related synucleinopathies that are characterized by accumulations of alpha-synuclein in Lewy bodies. Recent identification of mutations in genes linked to lysosomal function and neurodegeneration has offered a unique opportunity to directly examine the role of lysosomes in disease pathogenesis. Mutations in lysosomal membrane protein ATP13A2 (PARK9) cause familial Kufor-Rakeb syndrome characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While previous data suggested a role of ATP13A2 in alpha-synuclein misfolding and toxicity, the mechanistic link has not been established. Here we report that loss of ATP13A2 in human fibroblasts from patients with Kufor-Rakeb syndrome or in mouse primary neurons leads to impaired lysosomal degradation capacity. This lysosomal dysfunction results in accumulation of alpha-synuclein and toxicity in primary cortical neurons. Importantly, silencing of endogenous alpha-synuclein attenuated the toxicity in ATP13A2-depleted neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least in part via the accumulation of alpha-synuclein. Our findings implicate lysosomal dysfunction in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of alpha-synuclein represent important therapeutic strategies for this disorder. |
