Topics: Huntington's disease, Huntingtin, Striatum Pages: 7 (2607 words) Published: November 29, 2012
Huntington’s disease is an autosomal dominant (Harper et al, 1991) neurodegenerative disorder characterized by involuntary movements, cognitive loss, and psychiatric problems as described by Martin and Gusella (1986). These symptoms are related to the death of medium spiny projection neurons in the caudate nucleus, putamen, and the cortex (Reiner et al, 1988). In later stages of the disease, even areas such as the hippocampus and hypothalamus gets affected as well (Kassubek et al, 2004). Huntington’s disease has a prevalence rate of approximately 1 in 10,000 Caucasian populations (Harper et al, 1991). Patients with Huntington’s disease most typically display a choreic movement disorder involving involuntary writhing movements observed by George Huntington himself. The age of onset of Huntington’s disease seem to be normally distributed around the average age of 35 to 42, with small number of cases developing in patients younger than 20 years of age or older than 60 years of age (Andrew et al, 1993). The majority of juvenile patients, whose disease onset are at age 20 years or less, have inherited the paternally defected gene (Andrew et al, 1993). Patients usually died within 15 to 20 years of disease onset. Gusella et al (1983) first determined the location of the genetic mutation in Huntington’s disease to be the short arm of chromosome 4. It was after another 10 years did the researchers of The Huntington’s Disease Collaborative Research Group (1993) able to discover that a gene in chromosome 4 containing a trinucleotide repeat of CAG was abnormally expanded in diseased individuals. The IT15 (interesting transcript 15) gene, dubbed the huntingtin gene by the group, codes for the huntingtin gene. This CAG repeat, which translates into a poly-glutamine stretch, is highly polymorphic among the population ranging from 11 to 34 copies on normal individuals. However, in individuals with Huntington’s disease it expanded to more than 42 repeats and increasing to upwards of 100 (The Huntington’s Disease Collaborative Research Group, 1993). This provides evidence showing that the mutant huntingtin protein seems to be toxic to its native cells and confers a disease state to individuals with an extended length of repeats. There is also a correlation between the CAG length and disease onset as shown by Andrew et al (1993). The mutated elongated huntingtin protein is cut by enzymes into fragments and the fragments begin to form abnormal clusters, neuronal intranuclear inclusions (NIIs), inside cells. These clusters can also act to recruit normal proteins to adhere together as well (Davies et al, 1997). This was originally thought to cause the pathogenesis of Huntington’s disease. However, more recent studies have shown that the presence of NIIs is actually a coping response to the toxicity of mutant huntingtin proteins and acts to prolong the life of the cells and reduce intracellular mutant huntingtin in neighbouring neurons (Arrasate et al, 2004). The exact function of the wild-type huntingtin protein are unclear, however many efforts have been made in understanding its native functions. Nasir et al (1995) showed that homozygous huntingtin homologs in mice died before embryogenesis could occur and that heterozygotes displayed similar deficits as diseased human patients. Wild-type huntingtin is also crucial for establishing and maintaining neuronal identity, especially in cortex and striatum (Reiner et al, 2001). Current data can provide the conclusion that normal huntingtin protein has actions important for development in mammals. In vitro, wild-type huntingtin have been shown to act to protect brain cells from apoptotic stimuli, such as serum deprivation, mitochondrial toxins, or the transfection of death genes (Cattaneo et al, 2005). Wild-type huntingtin protein, not mutated, stimulates brain-derived neurotrophic factor (BDNF) production by acting at level of Bdnf transcription. BDNF is very important for survival of striatal...
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