Could successful (mitochondrial) networking help prevent Huntington's disease?
Polyglutamine expansions in huntingtin (Htt) are known to cause the profound neurodegenerative disorder, Huntington's disease (HD). Mitochondrial dysfunction has long been implicated in the pathophysiology of HD, but the underlying mechanism remains obscure. An article by Costa et al in this months edition describes a smooth mechanistic cascade from the well-accepted upstream event that mutant Htt is associated with Ca(2+) handling abnormalities, through to apoptotic neuronal death. The proposed cascade implicates calcineurin, activated by abnormal Ca(2+) levels, in the dephosphorylation of dynamin-1-like protein (Drp1), increasing its association with mitochondria and promoting fission, cristae disruption, cytochrome c release and apoptosis (Fig 1). Together with the recent reports of increased mitochondrial fission in striatal neurons from HD patients, the article by Costa et al provides a compelling case for the role of abnormal mitochondrial networking in HD pathogenesis.
REQUIMTE, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Jorge M A
JM
Oliveira
Robert N
RN
Lightowlers
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins