Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1
Open accessAbstract
Intracellular accumulation of mutant Huntingtin with expanded polyglutamine provides a context-dependent cytotoxicity critical for the pathogenesis of Huntington disease (Everett, C. M., and Wood, N. W. (2004) Brain 127, 2385-2405). Here we demonstrate that the accumulation of mutant Huntingtin is highly sensitive to the expression of beclin 1, a gene essential for autophagy. Moreover, we show that the accumulated mutant Huntingtin recruits Beclin 1 and impairs the Beclin 1-mediated long lived protein turnover. Thus, sequestration of Beclin 1 in the vulnerable neuronal population of Huntington disease patients might further reduce Beclin 1 function and autophagic degradation of mutant Huntingtin. Finally, we demonstrate that the expression of beclin 1 decreases in an age-dependent fashion in human brains. Because beclin 1 gene is haploid insufficient in regulating autophagosome function (Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G., and Levine, B. (2003) J. Clin. Invest. 112, 1809-1820; Yue, Z., Jin, S., Yang, C., Levine, A. J., and Heintz, N. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 15077-15082), we propose that the age-dependent decrease of beclin 1 expression may lead to a reduction of autophagic activity during aging, which in turn promotes the accumulation of mutant Htt and the progression of the disease.
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Decrease of some macroautophagy markers has been described in different tissues of rodents and in the aging human brain.
“decrease of some macroautophagy markers have been described in different tissues of rodents and in the aging human brain (Shibata et al., 2006)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Shibata et al., 2006
The section on Beclin 1 in post-mortem human brains reports that Beclin 1 mRNA and protein were about twofold lower in older than younger prefrontal cortex samples. The passages on rodent cells and mouse brains do not report an age-related decrease in macroautophagy markers across different rodent tissues, so that part of the claim is unsupported by our copy. (LLM, conf=0.87)
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- Yue, Z., Jin, S., Yang, C., Levine, A. J., and Heintz, N. (2003) Proc. Natl. Acad. Sci.
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- Authors
- Shibata, M., Lu, T., Furuya, T., Degterev, A., Mizushima, N., Yoshimori, T., MacDonald, M., Yankner, B., & Yuan, J.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- National Institute of Genetics (JP)
- Massachusetts General Hospital (US)
- Corresponding author
- Yuan, Junying
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 20
- Pages
- 14474-14485
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2160571070
- Cited by
- 458
- References
- 6
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 13 · 2023: 11 · 2022: 14 · 2021: 32 · 2020: 21 · 2019: 25 · 2018: 29 · 2017: 23 · 2016: 33 · 2015: 26 · 2014: 25 · 2013: 24 · 2012: 24
- FWCI
- 9.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- U.S. Public Health Service (R37-12859)
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke (NS 16367, NS32765, R01NS032765)
- 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
- mutant huntingtin, Beclin-1, autophagy, intracellular accumulation, Huntington's disease, autophagic degradation, age-related gene expression, neuronal vulnerability, haploinsufficiency
- MeSH terms
- Huntingtin Protein, Beclin-1, Adult, Aged, 80 and over, Aging, Animals, Brain, Gene Expression Regulation, Humans, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Nuclear Proteins, Proteins, Disease Progression, Apoptosis Regulatory Proteins, Mice
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