The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease
Open accessAbstract
As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.
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Dysregulation in many autophagic/lysosomal pathways occurs in the context of AD.
“a number of studies reporting dysregulation in many autophagic/lysosomal pathways in the context of AD [234,235]”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [234]
Increased pRb is present in the cytoplasm of neurons in the substantia nigra of PD patients compared to age-matched controls.
“Increased pRb, another important regulator of cell-cycle progression, was reported in the cytoplasm of neurons in the substantia nigra of PD patients compared to age-matched controls [234].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [234]
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References 217 · Cited by 190
Research works printed but not linked: 5
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- Authors
- Ihara, Y., Morishima-Kawashima, M., & Nixon, R.
- Affiliations
- Doshisha University (JP)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Ihara, Y.
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-04-04
- Volume
- 2
- Issue
- 8
- Pages
- a006361-a006361
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC3405832
- OpenAlex
- W2165152085
- Cited by
- 190
- References
- 217
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 6 · 2023: 11 · 2022: 10 · 2021: 14 · 2020: 12 · 2019: 9 · 2018: 13 · 2017: 21 · 2016: 16 · 2015: 16 · 2014: 16 · 2013: 19 · 2012: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Tokyo
- National Institute on Aging
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- ubiquitin-proteasome system, autophagy, lysosomal system, Alzheimer's disease, protein quality control, paired helical filaments, ubiquitination, neurodegeneration, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Autophagy, Disease Models, Animal, Humans, Lysosomes, Nerve Degeneration, Neurons, Endosomes, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Cellular Senescence, Disease Progression, Ubiquitin, Proteasome Endopeptidase Complex, Mice, Proteolysis
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