期刊
HUMAN MOLECULAR GENETICS
卷 16, 期 1, 页码 61-77出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddl440
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资金
- NCI NIH HHS [CA-62203] Funding Source: Medline
- NICHD NIH HHS [HD36081] Funding Source: Medline
- NINDS NIH HHS [NS42157-04, NS045283] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD036081] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [P30CA062203] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS045283, R01NS042157] Funding Source: NIH RePORTER
A truncated form of the Huntington's disease (HD) protein that contains the polyglutamine repeat, Httex1p, causes HD-like phenotypes in multiple model organisms. Molecular signatures of pathogenesis appear to involve distinct domains within this polypeptide. We studied the contribution of each domain, singly or in combination, to sub-cellular localization, aggregation and intracellular Ca2+ ([Ca2+](i)) dynamics in cells. We demonstrate that sub-cellular localization is most strongly influenced by the first 17 amino acids, with this sequence critically controlling Httex1p mitochondrial localization and also promoting association with the endoplasmic reticulum (ER) and Golgi. This domain also enhances the formation of visible aggregates and together with the expanded polyQ repeat acutely disrupts [Ca2+](i) levels in glutamate-challenged PC12 cells. Isolated cortical mitochondria incubated with Httex1p resulted in uncoupling and depolarization of these organelles, further supporting the idea that Httex1p-dependent mitochondrial dysfunction could be instrumental in promoting acute Ca2+ dyshomeostasis. Interestingly, neither mitochondrial nor ER associations seem to be required to promote long-term [Ca2+](i) dyshomeostasis.
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