Cited by 435Autophagy in Disease and TherapyAlzheimer's disease research and treatmentsCalcium signaling and nucleotide metabolism

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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

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Nixon, Ralph A., Rubinsztein, David C.·2024·Nature Reviews Molecular Cell Biology

DOI 10.1038/s41580-024-00757-5PMC PMC12239022

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Abstract

Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy-lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia. We also consider the strong impact of cellular ageing on lysosomes and autophagy as a tipping point for the late-age emergence of related neurodegenerative disorders. Many of these diseases have primary defects in autophagy, for example affecting autophagosome formation, and in lysosomal functions, especially pH regulation and calcium homeostasis. We have aimed to provide an integrative framework for understanding the central importance of autophagic-lysosomal function in neuronal health and disease.

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Authors: Nixon, R. A., & Rubinsztein, D. C.
Affiliations: Nathan Kline Institute for Psychiatric Research (US)
University of Cambridge (GB)
Corresponding author: Nixon, Ralph A.
ORCID: Nixon, Ralph A.
Rubinsztein, David C.
Venue: Nature Reviews Molecular Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2024-08-06
Volume: 25
Issue: 11
Pages: 926-946
ISSN: 1471-0072 (ISSN-L)
1471-0080
DOI: 10.1038/s41580-024-00757-5
PMC: PMC12239022
OpenAlex: W4401363901
Cited by: 435
References: 319
Citations by year: 2026: 260 · 2025: 160 · 2024: 14
FWCI: 26.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: cc-by
www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Reviews Molecular Cell Biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion, cc-by)
Apollo (University of Cambridge) (submittedVersion, cc-by)
Apollo (cc-by)
Funders: CHDI Foundation
Rainwater Charitable Foundation
Alzheimer's Society
National Institute for Health and Care Research ((NIHR203312)
Department of Health and Social Care
Parkinson's UK
Rosetrees Trust
UK Dementia Research Institute
Medical Research Council (NIHR203312)
NIHR Cambridge Biomedical Research Centre (NIHR 203312)
National Institute on Aging (P01AG017617, R01AG062376)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords: autophagy, lysosomes, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, neuronal aging, autophagosome formation, calcium homeostasis, protein aggregate clearance, lysosomal storage disease
MeSH terms: Autophagosomes, Animals, Autophagy, Humans, Lysosomes, Neurons, Neurodegenerative Diseases

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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

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