CHARACTERIZING POTASSIUM CHLORIDE CO-TRANSPORTER 2 (KCC2) PROTEIN INTERACTIONS IN HUNTINGTON'S DISEASE

KCC2 is the neuron specific member of the K⁺-Cl^- cotransporter family of proteins that maintains a low intracellular Cl^- concentration required for fast synaptic inhibition mediated by gamma-aminobutyric acid (GABA) in the central nervous system. Early in postnatal development, immature neurons express low levels of KCC2 resulting in high [Cl-]i and an excitatory GABA action. As development progresses, KCC2 expression is upregulated leading to reduced [Cl-]i and a shift to an inhibitory GABA action. Several neurological disorders including Huntington’s disease (HD) exhibit impaired synaptic inhibition and Cl^- regulation due to decreased KCC2 expression and function. While KCC2 is heavily regulated post-translationally, it is also evident that protein-protein interactions (PPIs) of KCC2 can modulate its expression and function. Identification of the KCC2 interactome can thus provide substantial insight into its function and serve as a valuable approach to characterize the pathological mechanisms underlying disease. While HD typically manifests in adults, recent evidence suggests that human and rodent HD brains exhibit aberrant neurodevelopment at time points that coincide with the developmental GABA switch. Characterizing changes in the KCC2 interactome before and after the GABA switch is thus a critical step towards elucidating the pathological mechanisms observed during the symptomatic phase of HD.