Lu, J., Periz, G., Lu, Y.N., Tang, Q., Liu, Y., Zhang, T., Shah, Y., Thombre, R., Aljumaah, R., Li, W., Mojsilovic-Petrovic, J., Ji, Y., Johnson, K., Kalb, R., Wang, J. (2019). L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control.  Nat. Neurosci. 22(6): 875--886.

FBrf0242831

Research paper

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.

PMC6588399 (PMC) (EuropePMC)