Molecular targets and therapeutic strategies in Huntington's disease.
This article provides an overview of the molecular mechanisms associated with striatal neuronal degeneration in Huntington's disease (HD), the most studied of the diseases caused by polyglutamine expansion. We discuss the current status of research in cellular and animal models of HD, in which protein aggregation, excitotoxicity, mitochondrial dysfunction, transcription deregulation, trophic factor starvation and the disruption of axonal transport appear to be key features for selective striatal neurodegeneration. We further emphasize some of the most promising current strategies in HD treatment. We delineate the molecular and cellular rationale underlying the development of new pharmaceutical interventions that offer new hope of future treatment for HD patients worldwide.
Rego
A Cristina
AC
Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. acrego@cnc.cj.uc.pt
de Almeida
Luís Pereira
LP
D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D042622:DNA Repeat Expansion / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000473:pathology; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; C097188:polyglutamine; D020169:Caspases