Huntington's disease (HD) is a progressive neurodegenerative disorder with an established genetic origin. Adult onset HD is characterized by motor dysfunction, cognitive decline and psychiatric disturbance (Ranen et al., 1993 and Harper, 1996). Initially symptoms include depression, irritable mood, and some minor involuntary movements (Young et al., 1986 and Harper, 1996). As the disease progresses, chorea becomes more evident. The most prominent characteristics of HD include a profound loss of neurons in the caudate nucleus and putamen, which together comprise the corpus striatum within the basal ganglia (Ross, 1995). HD is caused by an elongation of a polyglutamine tract in the N-terminal of the huntingtin gene placing it into the trinucleotide repeat disorders family of neurologic diseases.
[...] The circuitry of the basal ganglia is often divided into two major pathways, the direct and the indirect pathways (Willard, 1993). The circuit starts with glutamatergic neurons from the cerebral cortex projecting to the corpus striatum. Then, there are two pathways leaving the striatum and projecting to the internal globus pallidus. The direct pathway involves GABAergic and substance P fibers directly innervating the internal globus pallidus. In contrast, in the indirect pathway, GABAergic and enkephalinergic neurons first project to the external globus pallidus, then to the subthalamus with GABAergic fibers, and finally to the internal globus pallidus with glutamatergic fibers. [...]
[...] Reiner Albin RL, Anderson KD, D'Amato CJ, Penney JB, and Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proceedings of the National Academy of Sciences USA 85:5733-5737 Ross CA (1995) When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 19;15:493–496 Saudou Finkbeiner Devys D and Greenberg, ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66 Sawa Tomoda Bae BI (2003) Mechanisms of neuronal cell death in Huntington's disease. [...]
[...] The cause of neuronal cell death in HD is unknown, and several theories have been proposed to explain pathogenesis. The major pathogenic mechanisms of HD include transcriptional dysregulation, caspase cascade activation and mitochondrial toxicity. Since Saudou et al. have shown that inclusions are not the cause of degeneration, aggregate formation causing cleavage and subsequent entry of mutant truncated huntingtin into the nucleus appears to be crucial in leading to mechanisms of apoptotic cell death (Saudou et al., 1998). It has now been suggested that the inclusions are an attempt by the cells to sequester a toxic fragment rather than the primary cause of cell death (Saudou et al., 1998). [...]
[...] Nat Genet 16:44–53 Kim, YJ, Yi, Sapp, Wang, Cuiffo, Kegel, KB, Qin, ZH, Aronin, N and DiFiglia, M Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis Proc Natl Acad Sci USA 98:12784–12789 Li SH, Lam Cheng AL, and Li XJ (2000) Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum Mol Genet 9:2859–2867 Liu YF (1998) Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. [...]
[...] Ann Neurol 31: 119-130 Beal, MF (1999) Does impariment of energy metabolism result in excitotoxic neuronal Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, and Ross CA (1998) Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 4:387-97 Boutell JM, Wood JD, Harper PS, and Jones AL (1998) Huntingtin interacts with cystathionine beta-synthase. Hum Mol Genet 7:371-8 Brouillet Hantraye Ferrante RJ, Dolan Leroy-Willig Kowall NW, Beal MF (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. [...]
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