L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control

Jiayin Lu, Goran Periz, Yu Ning Lu, Qing Tang, Yang Liu, Tao Zhang, Yajas Shah, Ravi Thombre, Reham Aljumaah, Weixin Li, Jelena Mojsilovic-Petrovic, Yon Ji, Kenji Johnson, Robert Kalb, Jiou Wang

Research output: Contribution to journalArticlepeer-review


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

Original languageEnglish (US)
Pages (from-to)875-886
Number of pages12
JournalNature neuroscience
Issue number6
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • Neuroscience(all)


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