Huntington's disease: From molecular basis to therapeutic advances.
Huntington's disease is an autosomal dominant genetic neurodegenerative disorder, which is characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss. The disease is caused by pathological CAG-triplet repeat extension(s), encoding polyglutamines, within the gene product, huntingtin. Huntingtin is ubiquitously expressed through the body and is a protein of uncertain molecular function(s). Mutant huntingtin, containing pathologically extended polyglutamines causes the earliest and most dramatic neuropathologic changes in the neostriatum and cerebral cortex. Extended polyglutamines confer structural conformational changes to huntingtin, which gains novel properties, resulting in aberrant interactions with multiple cellular components. The diverse and variable aberrations mediated by mutant huntingtin perturb many cellular functions essential for neuronal homeostasis and underlie pleiotropic mechanisms of Huntington's disease pathogenesis. The only approved drug for Huntington's disease is a symptomatic treatment, tetrabenazine; thus, novel neuroprotective strategies, slowing, blocking and possibly reversing disease progression, are vital for developing effective therapies.
Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany. Krobitsc@molgen.mpg.de
Sylvia
S
Krobitsch
Aleksey G
AG
Kazantsev
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D009154:Mutation; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011487:Protein Conformation; D013747:Tetrabenazine / Q000627:therapeutic use; D018911:Trinucleotide Repeats / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D013747:Tetrabenazine