Exploring Kir4.2 as a Novel Therapeutic Target in Parkinson’s Disease — The Association Specialists
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Exploring Kir4.2 as a Novel Therapeutic Target in Parkinson’s Disease (21551)

Xiaoyi Chen 1 2 , Benjamin Garland 1 2 , zhiqiang shen 1 2 , Rocio Finol-Urdaneta 3 , Mo Chen 2 4 , Alex Sykes 2 , Bingmiao Gao 5 , Jamila Iqbal 2 , Des Richardson 1 2 , David J Adams 3 , George Mellick 1 2 , Linlin Ma 1 2
  1. School of Environment and Science, Griffith University, Nathan, QLD, Australia
  2. Institute for Biomedicine and Glycomics, Griffith University, Nathan, QLD, Australia
  3. School of Medical, Indigenous and Health Sciences, Molecular Horizons Research Institute University of Wollongong, Wollongong, NSW 2522, Australia
  4. Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University,, Nathan, 4111, QLD, Australia
  5. Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University , Haikou 571199, China

Parkinson’s Disease (PD) is a notoriously difficult medical challenge due to its highly complex nature, involving multiple and incompletely characterized cellular and molecular mechanisms. Many critical breakthroughs toward understanding PD’s etiology have emerged from studying rare families with inherited forms of the disease. These studies identified key proteins crucial in the disease process and have spurred the development of new drugs.

Through a genetic linkage study, we identified a genetic variant, KCNJ15p.R28C, which strongly segregates with PD in a large family with familial PD. This variant was also found in other sporadic PD patients, underscoring the functional role of KCNJ15-encoded protein, the inwardly rectifying K+ channel Kir4.2, in PD pathogenesis.

Our in-silico analyses employing multiple bioinformatics tools indicated that KCNJ15p.R28C (Kir4.2R28C) is a deleterious variant. Indeed, patch clamp studies revealed that the mutation results in a complete loss of channel function with a strong dominant-negative effect. The loss of function in Kir4.2R28C is partially due to reduced expression of the mutant protein. Further investigation into the underlying mechanisms showed that the Kir4.2R28C mutant is unstable and more prone to lysosomal-mediated degradation with sacrificed plasma membrane trafficking capacity.

These findings are corroborated by our in vivo studies employing a newly developed KCNJ15-/-mouse model, which exhibits Parkinson’s traits, such as abnormal motor coordination, balance issues, and impaired special memory and learning capacity.

This study represents the first effort to explore the molecular mechanisms linking Kir4.2 and PD pathogenesis, highlighting Kir4.2 as a novel biological target for this devastating disease.