ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function.

Proceedings of the National Academy of Sciences of the United States of America
Josephine J WuMervyn J Monteiro

Abstract

Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/...Continue Reading

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Citations

Sep 24, 2020·The Biochemical Journal·Tongyin ZhengCarlos A Castañeda
Oct 9, 2020·Acta Neuropathologica Communications·Shaoteng WangMervyn J Monteiro
Sep 4, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Thuy P Dao, Carlos A Castañeda
Dec 17, 2020·American Journal of Physiology. Cell Physiology·Amity F EatonDennis Brown
Jan 5, 2021·Frontiers in Cellular Neuroscience·Silvia GiovedìFabrizia Claudia Guarnieri
Dec 6, 2020·The Journal of Biological Chemistry·Alexandra M WhiteleyDaniel Finley
Mar 30, 2021·Brain Pathology·Nicole R HigginsMervyn J Monteiro
May 1, 2021·International Journal of Molecular Sciences·Wenjuan ZhangCao Huang
Jun 1, 2021·Autophagy·Jason P ChuaSami J Barmada
Jul 26, 2021·The Journal of Biological Chemistry·Nathaniel SafrenSami J Barmada
Jul 18, 2021·The FEBS Journal·Brian C LinMervyn J Monteiro
Dec 2, 2020·Matrix Biology : Journal of the International Society for Matrix Biology·Linlin LeiKonstanze F Winklhofer
Jun 16, 2021·Journal of Neurochemistry·Julia F RileyCarlos A Castañeda

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