Final answer:
The problem with the mutant huntingtin protein in Huntington's Disease is that it contains an expanded sequence of glutamine residues due to a genetic mutation, leading to neuronal dysfunction and cell death.
Step-by-step explanation:
The central issue with the mutant huntingtin protein associated with Huntington's Disease (HD) is that it contains an abnormally long sequence of glutamine residues. This alteration is due to a mutation in the gene responsible for encoding the huntingtin protein. This genetic modification leads to the production of a mutant protein that significantly disrupts neuronal functions. A critical consequence of this includes the dysregulation of NMDA receptors, particularly at extrasynaptic sites. When activated, these extrasynaptic NMDA receptors contribute to increased intracellular calcium levels, which then initiate harmful downstream effects. Such effects include mitochondrial membrane potential disruption and, ultimately, neuronal cell death. Furthermore, the loss of GABAergic medium-sized spiny neurons exacerbates the condition, manifesting in physical, psychological, and cognitive symptoms like involuntary movements and cognitive decline.