Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy
Open accessAbstract
An expansion of polyglutamines in the N terminus of huntingtin causes Huntington's disease (HD) and results in the accrual of mutant protein in the nucleus and cytoplasm of affected neurons. How mutant huntingtin causes neurons to die is unclear, but some recent observations suggest that an autophagic process may occur. We showed previously that huntingtin markedly accumulates in endosomal-lysosomal organelles of affected HD neurons and, when exogenously expressed in clonal striatal neurons, huntingtin appears in cytoplasmic vacuoles causing cells to shrink. Here we show that the huntingtin-enriched cytoplasmic vacuoles formed in vitro internalized the lysosomal enzyme cathepsin D in proportion to the polyglutamine-length in huntingtin. Huntingtin-labeled vacuoles displayed the ultrastructural features of early and late autophagosomes (autolysosomes), had little or no overlap with ubiquitin, proteasome, and heat shock protein 70/heat shock cognate 70 immunoreactivities, and altered the arrangement of Golgi membranes, mitochondria, and nuclear membranes. Neurons with excess cytoplasmic huntingtin also exhibited increased tubulation of endosomal membranes. Exogenously expressed human full-length wild-type and mutant huntingtin codistributed with endogenous mouse huntingtin in soluble and membrane fractions, whereas human N-terminal huntingtin products were found only in membrane fractions that contained lysosomal organelles. We speculate that mutant huntingtin accumulation in HD activates the endosomal-lysosomal system, which contributes to huntingtin proteolysis and to an autophagic process of cell death.
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CTSD is considered a key protease in the lysosomal degradation of many pathogenic proteins in addition to APP metabolites, including α-synuclein and huntingtin.
“CTSD is considered as a key protease in the lysosomal degradation of many pathogenic proteins in addition to APP metabolites, including ␣-synuclein and huntingtin (Kegel et al., 2000;Sevlever et al., 2008).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Kegel et al., 2000
The Abstract reports that huntingtin-containing vacuoles incorporated cathepsin D, and the Discussion proposes the endosomal–lysosomal pathway as a route for huntingtin removal. The paper does not establish that CTSD is a key protease responsible for degrading huntingtin, and it does not address CTSD-mediated degradation of α-synuclein or APP metabolites. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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- Authors
- Kegel, K. B., Kim, M., Sapp, E., McIntyre, C., Castaño, J. G., Aronin, N., & DiFiglia, M.
- Affiliations
- Massachusetts General Hospital (US)
- Consejo Superior de Investigaciones Científicas (ES)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-10-01
- Volume
- 20
- Issue
- 19
- Pages
- 7268-7278
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772788
- OpenAlex
- W1940885739
- Cited by
- 533
- References
- 0
- Citations by year
- 2026: 1 · 2025: 19 · 2024: 18 · 2023: 6 · 2022: 11 · 2021: 24 · 2020: 30 · 2019: 18 · 2018: 17 · 2017: 12 · 2016: 27 · 2015: 19 · 2014: 21 · 2013: 26 · 2012: 29
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (T32 AG00222, T32AG000222)
- National Institute of Neurological Disorders and Stroke (R01NS035711, R01NS038194, P50NS016367)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- huntingtin, Huntington's disease, polyglutamine expansion, autophagy, endosomal-lysosomal system, cathepsin D, autophagosomes, autolysosomes, cytoplasmic vacuoles, striatal neurons, neuronal cell death, Golgi membranes
- MeSH terms
- Huntingtin Protein, Animals, Autophagy, Cathepsin D, Cell Nucleus, Cells, Cultured, Clone Cells, Corpus Striatum, Cytoplasm, Huntington Disease, Hybrid Cells, Lysosomes, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Endosomes, Subcellular Fractions, Transfection, Vacuoles, Blotting, Western, Mice
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