title: Prospects for neuroprotective therapies in prodromal Huntington's disease.
abstract: Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric disturbances, and a movement disorder. The genetic cause of the illness is a CAG repeat expansion in the huntingtin gene, which leads to a polyglutamine expansion in the huntingtin protein. The exact mechanism by which mutant huntingtin causes HD is unknown, but it causes abnormalities in gene transcription as well as both mitochondrial dysfunction and oxidative damage. Because the penetrance of HD is complete with CAG repeats greater than 39, patients can be diagnosed well before disease onset with genetic testing. Longitudinal studies of HD patients before disease onset have shown that subtle cognitive and motor deficits occur as much as 10 years before onset, as do reductions in glucose utilization and striatal atrophy. An increase in inflammation, as shown by elevated interleukin-6, occurs approximately 15 years before onset. Detection of these abnormalities may be useful in defining an optimal time for disease intervention to try to slow or halt the degenerative process. Although reducing gene expression with small interfering RNA or short hairpin RNA is an attractive approach, other approaches targeting energy metabolism, inflammation, and oxidative damage may be more easily and rapidly moved into the clinic. The recent PREQUEL study of coenzyme Q10 in presymptomatic gene carriers showed the feasibility of carrying out clinical trials to slow or halt onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies that could be utilized in presymptomatic HD.
authors.affiliation: Brain and Mind Research Institute, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.forename: Ashu
authors.initials: A
authors.lastname: Johri
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005820:Genetic Testing; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000628:therapy*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D014451:Ubiquinone; C024989:coenzyme Q10
keywords: PGC-1alpha; SIRT1; bezafibrate; coenzyme Q10; presymptomatic Huntington's disease