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

Overview

Significance; ; Mutations in; UBQLN2; cause amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 regulates proteostasis by clearing misfolded proteins from cells through the proteasome and autophagy degradation pathways. Here, we report on defects in autophagy that results from knockout or expression of WT and ALS/FTD mutant UBQLN2 proteins in cells and mice. We show that loss of UBQLN2 reduces expression of ATP6v1g1, a critical subunit of the ATPase pump that regulates vacuolar acidification and is required for the maturation of autophagosomes. We show that WT but not ALS/FTD mutant UBQLN2 proteins can rescue the acidification defect. Furthermore, WT but not ALS/FTD mutant UBQLN2 proteins bind and stimulate ATP6v1g1 biogenesis, suggesting an important role played by UBQLN2 in V-ATPase regulation.;

Wu JJ; Cai A; Greenslade JE; Higgins NR; Fan C; Le NTT; Tatman M; Whiteley AM; Prado MA; Dieriks BV