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Nat Neurosci. 2019 Jun;22(6):875-886. doi: 10.1038/s41593-019-0384-5. Epub 2019 May 6.

L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control.

Author information

1
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
2
Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
3
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
4
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. jiouw@jhmi.edu.
5
Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. jiouw@jhmi.edu.

Abstract

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.

PMID:
31061493
PMCID:
PMC6588399
[Available on 2019-11-06]
DOI:
10.1038/s41593-019-0384-5
[Indexed for MEDLINE]

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