Mellick, G. D. | bioRxiv Science

bioRxiv2026

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

A critical barrier to therapeutic development in Parkinsons disease (PD) is the lack of endogenous genetic models that spontaneously recapitulate the diseases 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 -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.

neuroscience↗

bioRxiv2024

Parkinson's Disease-Linked Kir4.2 Mutation R28C Leads to Loss of Ion Channel Function

Parkinsons disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation, and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD-linked genetic mutation in the KCNJ15 gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four-generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of the KCNJ15p.R28C (Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2-overexpressing HEK293T cells as a model, we investigated how the mutation affects the channels functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes, and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28C mutation results in loss of channel function with significant dominant-negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild-type (Kir4.2WT). We observed that both Kir4.2WT and Kir4.2R28C proteins undergo glycosylation during the post-translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28C mutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28C mutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WT channel, which potentially elucidates its role in the pathogenesis of PD. Key Points[tpltrtarr] Inwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinsons disease (PD) [tpltrtarr]We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi- generational pedigree. [tpltrtarr]This study confirms Kir4.2R28C as a loss-of-function mutation with significant dominant- negative effects, impairing channel activity even in heterozygous conditions. [tpltrtarr]The Kir4.2R28C mutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking in in vitro cell models.

cell biology↗