Journal
AUTOPHAGY
Volume 4, Issue 1, Pages 85-87Publisher
LANDES BIOSCIENCE
DOI: 10.4161/auto.5172
Keywords
Parkinson's disease; autophagy; aggresome; inclusion body; misfolded proteins; parkin; lysine-63; ubiquitination; HDAC6
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [F31NS054597, R01NS050650] Funding Source: NIH RePORTER
- NINDS NIH HHS [R01 NS050650-03, R01 NS050650-01A1, R01 NS050650, R01 NS050650-02, NS050650, F31 NS054597-02, F31 NS054597-01, F31 NS054597, NS054597] Funding Source: Medline
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Pathological inclusions containing misfolded proteins are a prominent feature common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In cultured cells, when the production of misfolded proteins exceeds the capacity of the chaperone refolding system and the ubiquitin-proteasorne degradation pathway, misfolded proteins are actively transported along microtubules to pericentriolar inclusions called aggresomes. The aggresomes sequester potentially toxic misfolded proteins and facilitate their clearance by autophagy. The molecular mechanism(s) that targets misfolded proteins to the aggresome-autophagy pathway is mostly unknown. Our recent work identifies parkin-mediated K63-linked polyubiquitination as a signal that couples misfolded proteins to the dynein motor complex via the adaptor protein histone deacetylase 6 and thereby promotes sequestration of misfolded proteins into aggresomes and subsequent clearance by autophagy. Our findings provide insight into the mechanisms underlying aggresome formation and suggest that parkin and K63-linked polyubiquitination may play a role in the autophagic clearance of misfolded proteins.
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