| First Author | Lu J | Year | 2019 |
| Journal | Nat Neurosci | Volume | 22 |
| Issue | 6 | Pages | 875-886 |
| PubMed ID | 31061493 | Mgi Jnum | J:281537 |
| Mgi Id | MGI:6378264 | Doi | 10.1038/s41593-019-0384-5 |
| Citation | Lu J, et al. (2019) L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control. Nat Neurosci 22(6):875-886 |
| abstractText | 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. |
