Abstract

Misfolded protein toxicity and failure of protein quality control underlie neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we identified Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1) as a previously unknown regulator of protein quality control, the loss of which protected against the proteotoxicity of mutant SOD1 or C9orf72 dipeptide repeat proteins. L3MBTL1 acts by regulating p53-dependent quality control systems that degrade misfolded proteins. SET domain-containing protein 8 (SETD8), a L3MBTL1-associatd p53-binding protein, also regulated clearance of misfolded proteins and was increased by proteotoxicity-associated stresses in mammalian cells. Both L3MBTL1 and SETD8 were up-regulated in the central nervous systems of mouse models of ALS and human ALS/FTD patients. The role of L3MBTL1 in protein quality control is conserved from C. elegans to mammalian neurons. These results indicate a previously unrecognized pathway in both normal stress response and proteotoxicity-associated neurodegenerative diseases.

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