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Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Alexander V Panov1, Claire-Anne Gutekunst, Blair R Leavitt
1Department of Neurology, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, Georgia 30322, USA.
Insights
Huntington's disease (HD) involves mitochondrial dysfunction. Mutant huntingtin protein directly impairs mitochondrial calcium handling, a defect occurring early in the disease process.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG triplet repeat expansion in the huntingtin gene.
- The precise mechanisms linking mutant huntingtin protein (Htt) to neurodegeneration are not fully understood.
Purpose of the Study:
- To investigate the role of mitochondria in Huntington's disease pathogenesis.
- To determine if mitochondrial dysfunction is an early event in HD and if it is directly caused by mutant huntingtin.
Main Methods:
- Assessed mitochondrial membrane potential and calcium response in lymphoblasts from HD patients and control subjects.
- Examined brain mitochondria from transgenic HD mouse models.
- Utilized electron microscopy to visualize mutant huntingtin.
- Replicated mitochondrial defects in vitro using a polyglutamine-containing fusion protein.
Main Results:
- Lymphoblast mitochondria from HD patients exhibited lower membrane potential and depolarized at lower calcium loads.
- Similar mitochondrial defects were observed in brain mitochondria of transgenic mice, preceding clinical symptoms.
- N-terminal mutant huntingtin was localized to neuronal mitochondrial membranes.
- In vitro experiments reproduced the observed mitochondrial calcium handling abnormalities.
Conclusions:
- Mitochondrial calcium handling abnormalities are an early feature of Huntington's disease pathogenesis.
- Mutant huntingtin protein appears to directly affect mitochondrial function.
- These findings suggest a direct role for mitochondrial dysfunction in the early stages of HD.
Abstract:
Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the mechanisms by which this mutant protein causes neurodegeneration remain unknown. Here we show that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. We found a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin, and this defect preceded the onset of pathological or behavioral abnormalities by months. By electron microscopy, we identified N-terminal mutant huntingtin on neuronal mitochondrial membranes, and by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, we reproduced the mitochondrial calcium defect seen in human patients and transgenic animals. Thus, mitochondrial calcium abnormalities occur early in HD pathogenesis and may be a direct effect of mutant huntingtin on the organelle.