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Could successful (mitochondrial) networking help prevent Huntington's disease?
Jorge M A Oliveira1, Robert N Lightowlers
1REQUIMTE, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
EMBO Molecular Medicine
|December 1, 2010
Summary
Mutant huntingtin protein in Huntington's disease (HD) disrupts calcium handling, leading to neuronal death through a cascade involving calcineurin and dynamin-1-like protein (Drp1) mediated mitochondrial fission.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by polyglutamine expansions in the huntingtin (Htt) protein.
- Mitochondrial dysfunction is a known factor in HD, but the precise mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanistic cascade linking mutant huntingtin to neuronal apoptosis.
- To investigate the role of calcium (Ca2+) handling abnormalities and mitochondrial dynamics in HD pathogenesis.
Main Methods:
- The study proposes a mechanistic cascade involving calcineurin activation by abnormal Ca2+ levels.
- This cascade leads to the dephosphorylation of dynamin-1-like protein (Drp1), affecting its mitochondrial association.
Main Results:
- Mutant Htt-associated Ca2+ dysregulation activates calcineurin.
- Activated calcineurin dephosphorylates Drp1, promoting its binding to mitochondria.
- This results in increased mitochondrial fission, cristae disruption, cytochrome c release, and apoptosis.
Conclusions:
- The findings present a mechanistic link between mutant huntingtin, calcium handling, and neuronal death in HD.
- Abnormal mitochondrial networking, specifically increased fission, is implicated as a key factor in HD pathogenesis.
- This research provides a compelling case for targeting mitochondrial dynamics in HD therapeutics.
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