Restoration of Shal/KV4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22
Year: 2025
Type: article
Abstract: Loss-of-function mutations in the human KCND3 gene encoding K V 4.3 K + channels are linked to the autosomal dominant neurodegenerative disease spinocerebellar ataxia type 19/22 (SCA19/22). Previous biophysical and biochemical analyses in vitro support the notion that the autosomal dominant inheritance pattern of SCA19/22 is associated with the dominant-negative effects of disease-causing K V 4.3 mutants on proteostasis of their wild-type (WT) counterpart. Herein we aimed to explore whether the disease-causing mutants might perturb protein expression of endogenous K V 4.3 channel in human cells, as well as contributing to in vivo pathomechanisms underlying motor impairments and neurodegeneration in an animal model of SCA19/22. Substantial reduction in human K V 4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human K V 4.3, in Drosophila led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human K V 4.3, but not K V 1.1 K + channel. Transgenic expression of SCA19/22-causing human K V 4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in Drosophila . Enhanced expression of the Drosophila molecular chaperones HSC70 and HSP83 in our fly model of SCA19/22 corrected Shal protein deficit, locomotor dysfunction, and neurodegeneration. Overexpression of Hsp90β also upregulated endogenous human K V 4.3 protein level in patient-derived skin fibroblasts. Our findings highlight Drosophila as a suitable animal model for studying K V 4.3 channelopathy in vivo, and accentuate a critical role of defective K V 4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22.
Authors: Cheng-Tsung Hsiao, Ssu-Ju Fu, Kai-Min Cheng, Hsiang Lo, Chih-Yung Tang, Chih-Chiang Chan, Chung-Jiuan Jeng
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
Awards: Protein Biosynthesis and Degradation Mechanisms of Kv4.3 Channels, Translational Research of Sca36: Explore the Molecular Mechanisms, Investigate the Therapeutic Targets, and Characterize the Clinical Features, G3489096787, Rab27-Mediated Lifespan Regulation in Drosophila Nervous System: Characterization of Neuronal Intracellular Machinery and Identification of Cell Non-Autonomous Components, Mechanistic Investigation of Smpd4 in Regulating the Lamina-Associated Domains and Microcephaly
OpenAlex ID: W4409864425