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Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells
F Trettel1, D Rigamonti, P Hilditch-Maguire
1Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
Human Molecular Genetics
|November 25, 2000
Summary
Huntington's disease (HD) involves mutant huntingtin protein's toxic gain of function. This study reveals mutant STHdh(Q111) cells disrupt striatal cell homeostasis via novel mechanisms, implicating stress pathways in HD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a lengthened polyglutamine tract in the huntingtin protein.
- The mutant huntingtin protein exhibits a dominant toxic gain of function, leading to striatal neuron degeneration.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the toxic gain of function of mutant huntingtin.
- To identify cellular pathways disrupted by mutant huntingtin in striatal cells.
Main Methods:
- Comparison of striatal cell lines from wild-type and Hdh(Q111) knock-in embryos.
- Localization studies of full-length huntingtin variants using epitope accessibility.
- Phenotypic analysis of mutant STHdh(Q111) cells.
Main Results:
- Mutant huntingtin localized to nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking.
- Mutant STHdh(Q111) cells displayed dominant phenotypes distinct from huntingtin deficiency or excess.
- These phenotypes suggest a disruption of striatal cell homeostasis by a mechanism separate from huntingtin's normal function.
Conclusions:
- The mutant huntingtin protein disrupts striatal cell homeostasis through a novel mechanism.
- Elevated p53, endoplasmic reticulum stress, and hypoxia are implicated as potential stress pathways in Huntington's disease pathogenesis.