The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis
Open accessAbstract
The Huntington's disease (HD) mutation is a polyglutamine expansion in the N-terminal region of huntingtin (N-htt). How neurons die in HD is unclear. Mutant N-htt aggregates in neurons in the HD brain; expression of mutant N-htt in vitro causes cell death. Other in vitro studies show that proteolysis by caspase 3 could be important in regulating mutant N-htt function, but there has been no direct evidence for caspase 3-cleaved N-htt fragments in brain. Here, we show that N-htt fragments consistent with the size produced by caspase 3 cleavage in vitro are resident in the cortex, striatum, and cerebellum of normal and adult onset HD brain and are similar in size to the fragments seen after exogenous expression of human huntingtin in mouse clonal striatal neurons. HD brain extracts treated with active caspase 3 had increased levels of N-htt fragments. Compared with the full-length huntingtin, the caspase 3-cleaved N-htt fragments, especially the mutant fragment, preferentially segregated with the membrane fraction. Partial proteolysis of the human caspase 3-cleaved N-htt fragment by calpain occurred in vitro and resulted in smaller N-terminal products; products of similar size appeared when mouse brain protein extracts were treated with calpain. Results support the idea that sequential proteolysis by caspase 3 and calpain may regulate huntingtin function at membranes and produce N-terminal mutant fragments that aggregate and cause cellular dysfunction in HD.
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Cites
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Cited by
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
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Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
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Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
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Metadata
- Authors
- Kim, Y. J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K. B., Qin, Z.-H., Aronin, N., & DiFiglia, M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2001-10-23
- Volume
- 98
- Issue
- 22
- Pages
- 12784-12789
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2100715439
- Cited by
- 398
- References
- 30
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. https://app.cochat.ai/papers/10.1073/pnas.221451398
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- Kim, Y. J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K. B., Qin, Z.-H., Aronin, N., & DiFiglia, M. (2001). Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.221451398
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