Functional Analysis of VPS41-Mediated Neuroprotection in Caenorhabditis elegans and Mammalian Models of Parkinson's Disease

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Date
2012
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Society for Neuroscience
Abstract

Disruption of the lysosomal system has emerged as a key cellular pathway in the neurotoxicity of alpha-synuclein (alpha-syn) and the progression of Parkinson's disease (PD). A large-scale RNA interference (RNAi) screen using Caenorhabditis elegans identified VPS-41, a multidomain protein involved in lysosomal protein trafficking, as a modifier of alpha-syn accumulation and dopaminergic neuron degeneration (Hamamichi et al., 2008). Previous studies have shown a conserved neuroprotective function of human VPS41 (hVPS41) against PD-relevant toxins in mammalian cells and C. elegans neurons (Ruan et al., 2010). Here, we report that both the AP-3 (heterotetrameric adaptor protein complex) interaction domain and clathrin heavy-chain repeat domain are required for protecting C. elegans dopaminergic neurons from alpha-syn-induced neurodegeneration, as well as to prevent alpha-syn inclusion formation in an H4 human neuroglioma cell model. Using mutant C. elegans and neuron-specific RNAi, we revealed that hVPS41 requires both a functional AP-3 (heterotetrameric adaptor protein complex) and HOPS (homotypic fusion and vacuole protein sorting)-tethering complex to elicit neuroprotection. Interestingly, two nonsynonymous single-nucleotide polymorphisms found within the AP-3 interacting domain of hVPS41 attenuated the neuroprotective property, suggestive of putative susceptibility factors for PD. Furthermore, we observed a decrease in alpha-syn protein level when hVPS41 was overexpressed in human neuroglioma cells. Thus, the neuroprotective capacity of hVPS41 may be a consequence of enhanced clearance of misfolded and aggregated proteins, including toxic alpha-syn species. These data reveal the importance of lysosomal trafficking in maintaining cellular homeostasis in the presence of enhanced alpha-syn expression and toxicity. Our results support hVPS41 as a potential novel therapeutic target for the treatment of synucleinopathies like PD.

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Keywords
MUTANT ALPHA-SYNUCLEIN, LYSOSOMAL TRAFFICKING, LEWY BODIES, VPS41, AUTOPHAGY, DEGRADATION, PROTEASOME, TRANSPORT, PROTEINS, NEURONS, Neurosciences
Citation
Harrington, A. J., Yacoubian, T. A., Slone, S. R., Caldwell, K. A., & Caldwell, G. A. (2012). Functional Analysis of VPS41-Mediated Neuroprotection inCaenorhabditis elegansand Mammalian Models of Parkinson’s Disease. In The Journal of Neuroscience (Vol. 32, Issue 6, pp. 2142–2153). Society for Neuroscience. https://doi.org/10.1523/jneurosci.2606-11.2012