β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of CIC-7

JOURNAL OF MOLECULAR BIOLOGY

卷:432

Review

Lee, Ju-Hyun^1,2  Wolfe, Devin M.^1,5  Darji, Sandipkumar¹  McBrayer, Mary Kate^1,6  Colacurcio, Daniel J.^1,7  Kumar, Asok¹  Stavrides, Philip¹  Mohan, Panaiyur S.^1,2  Nixon, Ralph A.^1,2,3,4 

[1] Nathan S Kline Inst, Ctr Dementia Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA

[2] Langone Med Ctr, Dept Psychiat, New York, NY 10016 USA

[3] Langone Med Ctr, Dept Cell Biol, New York, NY 10016 USA

[4] NYU, Neurosci Inst, New York, NY 10016 USA

[5] Sanofi, Rare Dis Sci, Bridgewater Township, NJ USA

[6] PMV Pharma, Cranbury Township, NJ USA

[7] Dedham Grp, New York, NY USA

关键词: acidification;    chloride;    lysosome;    PKA;    RNA-seq;   

DOI  :  10.1016/j.jmb.2020.02.021

来源: Elsevier

【 摘 要 】

Lysosomal dysfunction is considered pathogenic in Alzheimer disease (AD). Loss of presenilin-1 (PSEN1) function causing AD impedes acidification via defective vacuolar ATPase (vATPase) V0a1 subunit delivery to lysosomes. We report that isoproterenol (ISO) and related beta 2-adrenergic agonists reacidify lysosomes in PSEN1 Knock out (KO) cells and fibroblasts from PSEN1 familial AD patients, which restores lysosomal proteolysis, calcium homeostasis, and normal autophagy flux. We identify a novel rescue mechanism involving Portein Kinase A (PKA)-mediated facilitation of chloride channel-7 (010-7) delivery to lysosomes which reverses markedly lowered chloride (Cl-) content in PSEN1 KO lysosomes. Notably, PSEN1 loss of function impedes Endoplasmic Reticulum (ER)-to-lysosome delivery of CIC-7. Transcriptomics of PSEN1deficient cells reveals strongly downregulated ER-to-lysosome transport pathways and reversibility by ISO, thus accounting for lysosomal - deficits that compound pH elevation due to deficient vATPase and its rescue by beta 2-adrenergic agonists. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through beta 2-adrenergic regulation of CIC-7, which can potentially be modulated therapeutically. Published by Elsevier Ltd.

【 授权许可】

Free