Selective Neuronal Vulnerability In Hd

Normal htt is expressed throughout the brain. The protein associates with microtubules, vesicular organelles, and mitochondria and is believed to be involved in organelle transport4. Mutant huntingtin (mhtt) is also widely expressed and appears to localize similarly to the normal protein5,6. Selective neuronal vulnerability cannot be explained by regional variation in htt expression, since the highest levels are found in cerebellum, which is relatively preserved in HD, whereas levels of htt in the striatum are less than in many other brain regions6. It was proposed that the mutation confers a "gain of function", producing an aberrant protein that is widely expressed, yet harmful only to some neurons5. In support of this, the phenotype of htt deficient mice, which is embryonic lethality, is unlike that of HD; during early development htt appears to have a role in nutrient supply, hematopoiesis, rRNA and mRNA biogenesis, perinuclear membrane trafficking, and iron metabolism (reviewed in ref. 7) - all findings that support the proposed role for htt in microtubule transport in mature animals. However, such data do not preclude a loss of other unrelated htt functions in mature animals. For example, conditional (postnatal day 5) htt knockout mice mature, but later develop a neurological phenotype7. Recent research demonstrates that htt interacts with a wide variety of neuronal proteins, many of which are enriched in the synapse. Investigations of novel and altered protein interactions within striatal neurons may help explain the selective vulnerability of these cells to a mutated protein that is ubiquitously expressed and crucial to the normal function of a variety of cell types.

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