text: Huntingtons disease (HD) is an inherited neurodegenerative disorder, with symptoms emerging during an individuals mid-adulthood. The most noticeable symptoms of this progressive disease are cognitive and motor impairments, as well as behavioral alterations.  These impairments can develop into dementia, chorea, and eventually death. At the molecular level, HD results from a mutation in the huntingtin protein (Htt). More specifically, there is an abnormal repetition of a CAG sequence towards the 5’-end of the gene, which then leads to the development of a toxic polyglutamine (polyQ) stretch in the protein. The mutated Htt protein affects an individual's proper neural functions by inhibiting the action of REST/NRSF.
  REST/NRSF is an important silencer element that binds to regulatory regions to control the expression of certain proteins involved in neural functions. The mechanistic actions of huntingtin are still not fully understood, but a correlation between Htt and REST/NRSF exists in HD development. By attaching to the REST/NRSF, the mutated huntingtin protein inhibits the action of the silencer element, and retains it in the cytosol. Thus, REST/NRSF cannot enter the nucleus and bind to the 21 base-pair RE-1/NRSE regulatory element. An adequate repression of specific target genes are of fundamental importance, as many are involved in the proper development of neuronal receptors, neurotransmitters, synaptic vesicle proteins, and channel proteins. A deficiency in the proper development of these proteins can cause the neural dysfunctions seen in Huntingtons disease. In addition to the lack of repression due to the inactive REST/NRSF, mutated huntingtin protein can also decrease the transcription of the brain-derived neurotropic factor (BDNF) gene. BDNF influences the survival and development of neurons in the central nervous system as well as the peripheral nervous system. This abnormal repression occurs when the RE1/NRSE region within the BDNF promoter region is activated by the binding of REST/NRSF, which leads to the lack of transcription of the BDNF gene.  Hence, the anomalous repression of the BDNF protein suggests a significant impact in Huntingtons disease.