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Huntington and the pathogenesis of Huntington’s disease (HD)

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  1. The primary region of neurodegeneration.
  2. The physiological functions of normal huntingtin.
  3. The cause of neuronal cell death in HD.
  4. The specific mechanism by which mutant huntingtin triggers the apoptotic caspase cascade.
  5. Pathogenic mechanism in HD.
  6. Evidence from animal studies using mitochondrial toxins.
  7. Conclusion.

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. [...]

[...] propose another pathway in which lengthening of CAG repeats weakens the interaction of HIP-1 and huntingtin to the extent that HIP-1 is released (Gervais et al., 2002). HIP-1 then interacts with Hippi, a protein that appears to be essential for forming a death-effector complex involving caspase-8, thereby setting off the apoptotic cascade. Combined, these studies suggest that mutant huntingtin can initiate activation of proapoptotic proteins by its increased CAG repeat length and decreased fragment size when cleaved; also cleavage of the protein exacerbates cellular toxicity. [...]

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