Huntington's disease, calcium, and mitochondria

Huntington's disease (HD) is caused by a mutation that increases the number of CAG repeats in the gene encoding for the protein Huntingtin (Htt). The mutation results in the pathological expansion of the polyQ stretch that is normally present within the N-terminal region of Htt. Even if Htt is ubiquitously expressed in tissues, the changes in the protein finally result in the clinical manifestation of motor and cognitive impairments observed in HD patients. The molecular ethiology of the disease is obscure: a number of cellular and animal models are used as essential tools in experimental approaches aimed at understanding it. Biochemical changes have been described that correlate with the malfunction of HD neurons (primarily in the striatum): consensus is gradually emerging that the dyshomeostasis of Ca(2+) and/or mitochondria stress are important factors in the linkage of the Htt mutation to the onset and progression of the disease. Here, we present a succint overview of the changes of Htt, of its possible effect on the transcription of critical genes and of its causative role in the disturbance of the neuronal Ca(2+) homeostasis. Particular emphasis will be placed on the role of mitochondria as key player in the molecular pathogenesis of the disease.