Huntington's disease (HD) is an autosomal dominant disorder caused by an 
expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, 
located on chromosome 4. When the number of trinucleotide CAG exceeds 40 
repeats, disease invariably is manifested, characterized by motor, cognitive, 
and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form 
(mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain 
regions are affected, the most vulnerable brain region is the striatum. Striatal 
medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the 
cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic 
mechanisms include, but are not restricted to, excitotoxicity, neurotrophic 
support deficits, collapse of the protein degradation mechanisms, mitochondrial 
dysfunction, transcriptional alterations, and disorders of myelin. Studies 
performed in cell type-specific and regionally selective HD mouse models 
implicate both MSN cell-autonomous properties and cell-cell interactions, 
particularly corticostriatal but also with non-neuronal cell types. Here, we 
review the intrinsic properties of MSNs that contribute to their selective 
vulnerability and in addition, we discuss how astrocytes, microglia, and 
oligodendrocytes, together with aberrant corticostriatal connectivity, 
contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous 
dysfunction in cell types other than MSNs. These findings have implications in 
terms of therapeutic strategies aimed at preventing neuronal dysfunction and 
degeneration.