Experimental therapeutics in transgenic mouse models of Huntington's disease

Huntingtin is a predominantly cytoplasmic protein that is found in neurons throughout the brain. The precise mechanism by which mutant huntingtin causes Huntington's disease (HD) is unknown but seems to be gain-of-function. The gene that encodes this protein can be mutated by expansion of a trinucleotide CAG repeat that encodes glutamine.N-terminal fragments of mutant huntingtin form toxic protein aggregates in neurons. Mutant huntingtin causes progressive neuronal dysfunction and death — HD is ultimately lethal.There are several different transgenic mouse models of HD that have enhanced the study of this disorder and the capacity to test promising therapeutics. Mouse models fall into three categories: (1) those that express full-length mutant human huntingtin; (2) those that express fragments of the mutant human huntingtin gene; and (3) those with CAG repeats inserted into the murine huntingtin gene.These mouse models have been used to investigate the role in HD of several processes that might be targeted therapeutically. These processes include: proteolysis of huntingtin; aggregation of huntingtin; apoptosis; transcriptional dysregulation; mitochondrial dysfunction; excitotoxicity; inflammation and oxidative damage; and transglutaminase activity.Vaccination against toxic proteins and transplantation of healthy brain tissue are two approaches to treatment that are under investigation.There is no consensus as to which type of mouse model is the best model of human HD. There have been few clinical trials of treatments in humans on which to base a comparative conclusion.