The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Deficiency of ATP13A2 Leads to Lysosomal Dysfunction, α-Synuclein Accumulation, and Neurotoxicity
Open accessAbstract
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 α-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 α-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 α-synuclein and toxicity in primary cortical neurons. Importantly, silencing of endogenous α-synuclein attenuated the toxicity in ATP13A2-depleted neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least in part via the accumulation of α-synuclein. Our findings implicate lysosomal dysfunction in the pathogenesis of Kufor–Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent important therapeutic strategies for this disorder.
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Cites
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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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α-Synuclein Locus Triplication Causes Parkinson's Disease
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Background
Cited by
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Menzies, F. M., Fleming, A., Caricasole, A., Bento, C. F., Andrews, S. P., Ashkenazi, A., Füllgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.01.022 · Cited by 1,134
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
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Parkinson disease: from pathology to molecular disease mechanisms
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Genetics in Parkinson disease: Mendelian versus non‐Mendelian inheritance
Hernandez, D. G., Reed, X., & Singleton, A. B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13593 · Cited by 448
“ATP13A2 is a multifunctional protein with 10 transmembrane domains that is hypothesized to play a role in both of the previously described PD pathways, endosome–lysosome dynamics (Dehay et al. 2012; Usenovic et al. 2012), and mitochondrial health (Grunewald et al.”
Background
Metadata
- Authors
- Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., & Krainc, D.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-03-21
- Volume
- 32
- Issue
- 12
- Pages
- 4240-4246
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W1968349206
- Cited by
- 291
- References
- 28
- FWCI
- 14.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., & Krainc, D. (2012). Deficiency of ATP13A2 Leads to Lysosomal Dysfunction, α-Synuclein Accumulation, and Neurotoxicity. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.5575-11.2012
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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
