Huntingtons disease (HD) is a rare and fatal neurodegenerative disorder that res

Question

Huntingtons disease (HD) is a rare and fatal neurodegenerative disorder that results in hyperkinesia. One of the issues that occurs as a result of Huntingons's is deficits in axonal transport. For Example, mutations in the huntingtin (Htt) gene result in the loss of anterograde transport of organelles such as mitochondria. Among their many functions, mitochondria are thought to sequester Ca2+ ions. You are working with an animal model of HD. You are recording the responses of neurons receiving synaptic inputs of cells in normal tissue and HD tissue. You note that these responses occur 3-5x more often in the HD tissue than that of normal tissue. Propose a mechansim wherein the Htt mutation could produce this increase in the responses of the HD neurons.

Explanation / Answer

HD disease is associated with the poly Q expansion leading to protein aggregation.

Wild type htt interacts with REST to promote BDNF transcription, BDNF promotes survival of corticol and striatal neurons. Mutant htt is associated with stratial and corticol neuron dysfunction results in excitotoxicity. Glial cells are involved in preventing this toxicity

poly Q expanded Htt cannot bind to REST/NRSF-----------repressor NRSF remains in nucleus--- BDNF transcription stops------trafficking and synthesis of BDNF stopped----results in striatal sensitivity .

Mutant Htt might be perturbing the cell-cell interactions, causing transcriptional misregulation and impaired transport.

Wild type Htt intercts with various transcription regulators such as CBP. CBP regulates histone acetylation and deacetylation therby controlling survival signals of neurons.But poly Q htt hinders binding with acetyltransferase.

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