Depletion of wild-type huntingtin in mouse models of neurologic diseases.

Huntington's disease (HD) is caused by a mutation in the gene encoding for huntingtin resulting in selective neuronal degeneration. Because HD is an autosomal dominant disorder, affected individuals have one copy of the mutant and one copy of the wild-type allele. Huntingtin has antiapoptotic properties and is critical for cell survival. However, the important role of wild-type huntingtin in both HD and other neurological diseases has not been fully recognized. We demonstrate disease-associated decreased levels of full-length huntingtin in brains of transgenic mouse models of HD, ischemia, trauma, and in spinal cord after injury. In addition, overexpression of wild-type huntingtin confers in vivo protection of neurodegeneration after ischemia. We propose that in HD, in addition to a toxic gain-of-function of mutant huntingtin, a parallel depletion of wild-type huntingtin results in a detrimental loss-of-function, playing an important role in disease progression.