Kir4.2 deficiency drives progressive Parkinson’s disease-like motor, cognitive and neuropathological phenotypes in mice

Abstract A critical barrier to therapeutic development in Parkinson’s disease (PD) is the lack of endogenous genetic models that spontaneously recapitulate the disease’s progressive, anatomically selective nigrostriatal pathology. Genetic studies have linked KCNJ15 , encoding the inwardly rectifying potassium channel Kir4.2, to familial PD via a loss-of-function dominant-negative variant; however, its mechanistic role in neurodegeneration remains unexplored. Here, we demonstrate that Kcnj15⁻/⁻ mice spontaneously develop a progressive PD-like phenotype, exhibiting a “coordination-first” motor syndrome, anxiety-like behavioural changes and spatial memory impairments. Crucially, neuropathology reveals selective degeneration of substantia nigra pars compacta neurons, sparing the ventral tegmental area, with marked microglial hyperactivation and phosphorylated α-synuclein accumulation, faithfully recapitulating the topography of human PD. Striatal transcriptomics further reveals upregulation of oligodendrocyte- and myelin-associated genes, implicating compensatory glial remodeling. These findings identify Kir4.2 as a critical homeostatic regulator of nigrostriatal integrity and establish the Kcnj15⁻/⁻ mouse as a new physiologically accurate and translatable model for PD research.