L3MBTL1 Regulates ALS/FTD-associated Proteotoxicity and Quality Control

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.