Loss of inwardly rectifying potassium channel Kir4.2 drives Parkinson's disease-like motor, cognitive and neuropathological features in mice

BackgroundParkinsons disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons, yet the molecular mechanisms initiating this cascade remain elusive. Genetic linkage studies have implicated KCNJ15 (encoding the inwardly rectifying potassium channel Kir4.2) in familial PD. Specifically, a mutation identified in a four-generation PD family acts as a loss-of-function variant with dominant-negative effects. However, the neural function of Kir4.2 and its role in driving neurodegeneration have not been established. MethodsTo investigate the pathological consequences of Kir4.2 loss, we performed longitudinal profiling of behavior, neuropathology, and transcriptomics in newly generated Kcnj15 knockout (Kcnj15-/-) mice and age and sex-matched WT littermates at 6 and 12 months of age. Motor, anxiety-like, and cognitive phenotypes were assessed with the behavioral battery (open field, accelerating rotarod, elevated balance beam, DigiGait, and Barnes maze tests), while neuropathological integrity of PD-relevant brain areas was evaluated via immunohistochemistry. Furthermore, bulk RNA-sequencing was performed on striatal tissue to identify downstream molecular signatures associated with channel loss. ResultsKcnj15-/- mice exhibited a progressive "coordination-first" motor syndrome, where deficits in dynamic balance and fine motor control emerged prior to gross locomotor impairments. This motor phenotype was accompanied by dynamic alterations in anxiety-like behavior and impaired spatial memory consolidation, mirroring prodromal cognitive decline. Neuropathologically, Kir4.2 loss triggered selective neurodegeneration in the substantia nigra pars compacta (SNpc), sparing the ventral tegmental area (VTA). This pathology was characterized by robust microglial hyperactivation and neuronal/microglial phosphorylated -synuclein accumulation. As such, these changes were indicative of disrupted proteostasis and a pro-inflammatory feed-forward loop. Striatal transcriptomics revealed up-regulation of oligodendrocyte- and myelin-associated genes, suggesting remodeling of glial support networks. ConclusionThese findings identify Kir4.2 as a critical homeostatic regulator of nigrostriatal circuit function. Kir4.2 dysfunction links ionic instability to a triad of neuroinflammation, synucleinopathy, and myelin plasticity, positioning Kir4.2 as a novel susceptibility factor in PD neurodegenerative vulnerability.