RRC ID 76887
Author Li D, Johmura Y, Morimoto S, Doi M, Nakanishi K, Ozawa M, Tsunekawa Y, Inoue-Yamauchi A, Naruse H, Matsukawa T, Takeshita Y, Suzuki N, Aoki M, Nishiyama A, Zeng X, Konishi C, Suzuki N, Nishiyama A, Harris AS, Morita M, Yamaguchi K, Furukawa Y, Nakai K, Tsuji S, Yamazaki S, Yamanashi Y, Shimada S, Okada T, Okano H, Toda T, Nakanishi M.
Title LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.
Journal Nat Aging
Abstract Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.
Volume 3(8)
Pages 1001-1019
Published 2023-8-1
DOI 10.1038/s43587-023-00464-4
PII 10.1038/s43587-023-00464-4
PMID 37474791
MeSH Animals DNA Helicases / metabolism DNA-Binding Proteins / genetics Ligases / metabolism Mice Motor Neurons* / metabolism Poly-ADP-Ribose Binding Proteins / metabolism RNA Helicases / metabolism RNA Recognition Motif Proteins / metabolism Ubiquitin* / metabolism
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385)
Human and Animal Cells HEV0120(HEV0120)