Prospects for neuroprotective therapies in prodromal Huntington's disease

Abhishek Chandra, Ashu Johri, M. Flint Beal
2014 Movement Disorders  
Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder which is 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, and both mitochondrial
more » ... ysfunction and oxidative damage. Since 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 IL-6, occurs about 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 siRNA or shRNA 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 the onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies which could be utilized in presymptomatic HD.
doi:10.1002/mds.25835 pmid:24573776 pmcid:PMC4624289 fatcat:lv3oofypczbcrpaiwsksn3y4ui