<p>Loss-of-function mutations in the human <i>KCND3</i> gene encoding K_V4.3&#xa0;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_V4.3 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_V4.3 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_V4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human K_V4.3, in <i>Drosophila</i> led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human K_V4.3, but not K_V1.1&#xa0;K⁺ channel. Transgenic expression of SCA19/22-causing human K_V4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in <i>Drosophila</i>. Enhanced expression of the <i>Drosophila</i> 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_V4.3 protein level in patient-derived skin fibroblasts. Our findings highlight <i>Drosophila</i> as a suitable animal model for studying K_V4.3 channelopathy in vivo, and accentuate a critical role of defective K_V4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22.</p>