4.7 Review

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

期刊

JOURNAL OF MOLECULAR BIOLOGY
卷 432, 期 8, 页码 2633-2650

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2020.02.021

关键词

acidification; chloride; lysosome; PKA; RNA-seq

资金

  1. NIH [P01AG017617]

向作者/读者索取更多资源

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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

Article Cell Biology

Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons

Pearl P. Y. Lie, Dun-Sheng Yang, Philip Stavrides, Chris N. Goulbourne, Ping Zheng, Panaiyur S. Mohan, Anne M. Cataldo, Ralph A. Nixon

Summary: Research reveals that mature lysosomes are restricted from entering axons in neurons, while transport carriers derived from the TGN supply lysosomal components to axons. In axons, most LAMP1 vesicles are weakly acidic TCs that shuttle lysosomal components bidirectionally.

CELL REPORTS (2021)

Article Neurosciences

Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Ju-Hyun Lee, Dun-Sheng Yang, Chris N. Goulbourne, Eunju Im, Philip Stavrides, Anna Pensalfini, Han Chan, Cedric Bouchet-Marquis, Cynthia Bleiwas, Martin J. Berg, Chunfeng Huo, James Peddy, Monika Pawlik, Efrat Levy, Mala Rao, Mathias Staufenbiel, Ralph A. Nixon

Summary: This study reveals unique autophagy dysregulation within neurons in Alzheimer's disease mouse models, particularly deficient autolysosome acidification, leading to the accumulation of autophagic vacuoles and the formation of flower-like structures called "PANTHOS," which may contribute to the development of senile plaques in Alzheimer's disease.

NATURE NEUROSCIENCE (2022)

Article Multidisciplinary Sciences

Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function

Pearl P. Y. Lie, Lang Yoo, Chris N. Goulbourne, Martin J. Berg, Philip Stavrides, Chunfeng Huo, Ju-Hyun Lee, Ralph A. Nixon

Summary: This study reveals the dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways associated with neurodegenerative diseases. The researchers found that degradative organelles in axons are selectively vulnerable to local calcium dysregulation, which is greatly influenced by the activation of TRPML1 channels. The study also identified a mechanism involving calcium-mediated JNK activation and DIC1B serine-80 phosphorylation that contributes to neuritic dystrophy.

SCIENCE ADVANCES (2022)

Editorial Material Cell Biology

Autolysosomal acidification failure as a primary driver of Alzheimer disease pathogenesis

Ju-Hyun Lee, Ralph A. Nixon

Summary: Genetic evidence has shown that lysosome dysfunction is linked to impaired autophagy-lysosomal pathway (ALP) flux in Alzheimer's disease (AD). This study discovered that autophagy dysfunction in mouse models of AD arises from early failure of autolysosome/lysosome acidification, which leads to downstream AD pathogenesis. These findings provide important insights into the sequence of events in plaque formation.

AUTOPHAGY (2022)

Article Cell Biology

Autophagy is a novel pathway for neurofilament protein degradation in vivo

Mala Rao, Sandipkumar Darji, Philip H. Stavrides, Chris N. Goulbourne, Asok Kumar, Dun-Sheng Yang, Lang Yoo, James Peddy, Ju-Hyun Lee, Aidong Yuan, Ralph A. Nixon

Summary: This study reveals the important role of autophagy in the degradation of neurofilament proteins in neurons, which may regulate the size of axon cytoskeleton and the responses of the neurofilament cytoskeleton to injury and disease.

AUTOPHAGY (2023)

Article Neurosciences

Posttranscriptional regulation of neurofilament proteins and tau in health and disease

Aidong Yuan, Ralph A. Nixon

Summary: Neurofilament and tau proteins are involved in regulating stability and functions of the microtubule network in axons, axonal transport, and learning and memory. Their expression is regulated at the transcriptional and posttranscriptional levels, with RNA-binding proteins and microRNAs playing important roles in their regulation through the 3'-untranslated regions of their mRNA.

BRAIN RESEARCH BULLETIN (2023)

Article Multidisciplinary Sciences

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration

Ying Jiang, John J. Alam, Stephen N. Gomperts, Paul Maruff, Afina W. Lemstra, Ursula A. Germann, Philip H. Stavrides, Sandipkumar Darji, Sandeep Malampati, James Peddy, Cynthia Bleiwas, Monika Pawlik, Anna Pensalfini, Dun-Sheng Yang, Shivakumar Subbanna, Balapal S. Basavarajappa, John F. Smiley, Amanda Gardner, Kelly Blackburn, Hui-May Chu, Niels D. Prins, Charlotte E. Teunissen, John E. Harrison, Philip Scheltens, Ralph A. Nixon

Summary: The study found that Rab5 is closely related to BFCN degeneration, and inhibiting Rab5 activity may be a method for treating related diseases. The use of neflamapimod reduced Rab5 activity, reversed endosomal pathology, and restored the number and morphology of BFCNs. The clinical trial in DLB patients showed that neflamapimod did not affect cognitive function, but there were improvements in functional mobility and dementia rating-scale, confirming its effect on BFCN function.

NATURE COMMUNICATIONS (2022)

Editorial Material Neurosciences

Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come

John J. Alam, Ralph A. Nixon

MOLECULAR NEURODEGENERATION (2023)

Article Biochemistry & Molecular Biology

Mycobacterium tuberculosis Ku Stimulates Multi-round DNA Unwinding by UvrD1 Monomers

Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt

Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.

JOURNAL OF MOLECULAR BIOLOGY (2024)