Distinct functional roles of Vps41-mediated neuroprotection in Alzheimer’s and Parkinson’s disease models of neurodegeneration
| Autor: | Kim A. Caldwell, Guy A. Caldwell, Edward F Griffin, Xiaohui Yan |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Parkinson's disease Dopamine Transgene Endocytic cycle Vesicular Transport Proteins Biology Neuroprotection Animals Genetically Modified 03 medical and health sciences Alzheimer Disease RNA interference Genetics medicine Animals Humans Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Genetics (clinical) Amyloid beta-Peptides ADP-Ribosylation Factors Mechanism (biology) Neurodegeneration Membrane Proteins Colocalization Parkinson Disease General Medicine medicine.disease Peptide Fragments Disease Models Animal 030104 developmental biology Gene Expression Regulation Nerve Degeneration alpha-Synuclein General Article Microtubule-Associated Proteins Neuroscience |
| Zdroj: | Human Molecular Genetics. |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddy308 |
| Popis: | Commonalities and, in some cases, pathological overlap between neurodegenerative diseases have led to speculation that targeting of underlying mechanisms might be of potentially shared therapeutic benefit. Alzheimer’s disease is characterized by the formation of plaques, composed primarily of the amyloid-β 1-42 (Aβ) peptide in the brain, resulting in neurodegeneration. Previously, we have shown that overexpression of the lysosomal-trafficking protein, human Vps41 (hVps41), is neuroprotective in a transgenic worm model of Parkinson’s disease, wherein progressive dopaminergic neurodegeneration is induced by α-synuclein overexpression. Here, we report the results of a systematic comparison of hVps41-mediated neuroprotection between α-synuclein and Aβ in transgenic nematode models of Caenorhabditis elegans. Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic Aβ neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with α-synuclein. Furthermore, the neuroprotective effect of ARL-8 or hVps41 appears to be dependent on their colocalization and the activity of ARL-8. Additionally, we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in Aβ toxicity with ARL-8. Further analysis of functional effectors of Aβ protein processing via the lysosomal pathway will assist in the elucidation of the underlying mechanism involving VPS-41-mediated neuroprotection. These results reveal functional distinctions in the intracellular management of neurotoxic proteins that serve to better inform the path for development of therapeutic interventions to halt neurodegeneration. |
| Databáze: | OpenAIRE |
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