10-06-2003, 09:30 PM
• Zhang Y, Li M, Drozda M, Chen M, Ren S, Mejia Sanchez RO, Leavitt BR, Cattaneo E, Ferrante RJ, Hayden MR and Friedlander RM (2003). Depletion of wild-type huntingtin in mouse models of neurologic diseases. J Neurochem 87:101-106. Summary: 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. Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Center For Molecular Medicine and Therapeutics and Departments of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Department of Pharmacological Sciences, University of Milano, Milano, Italy Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, Massachusetts and Boston University School of Medicine, Bedford, Massachusetts, USA Neurology, Pathology and Psychiatry Department, Boston University School of Medicine, Boston, Massachusetts, USA.