Ucp4  deficiency of cerebellar Purkinje cells induces bradykinesia

Abstract Although uncoupling protein 4 (UCP4) is the most abundant protein reported in the brain, the biological function of UCP4 in cerebellum and pathological outcome of UCP4 deficiency in cerebellum remain obscure. To evaluate the role of Ucp4 in the cerebellar Purkinje cells (PCs), we generated conditional knock-out of Ucp4 in PCs (Pcp2cre;Ucp4fl/fl mice) by breeding Ucp4fl/fl mice with Pcp2cre mice. PCR, western blot, double immunofluorescent staining and triple RNAscope in situ hybridization confirmed the specific ablation of Ucp4 in PCs in Pcp2cre;Ucp4fl/fl mice, and the reservation of Ucp2, the analog of Ucp4. Open field test, CatWalk analysis, rotarod and elevated plus-maze tests showed that Pcp2cre;Ucp4fl/fl mice displayed a characteristic bradykinesia in the spontaneous movements, and such bradykinesia disorder was not deteriorated in harmaline-induced tremor application. The electromyogram recordings detection on gastrocnemius muscle excluded the possibility of hypotonia in Pcp2cre;Ucp4fl/fl mice. And the electrical patch clamp recordings showed the altered properties of both spontaneous and evoked firings in PCs of Pcp2cre;Ucp4fl/fl mice. Also, the knockdown of Ucp4 significantly increased reactive oxygen species generation in the cerebellum. The present study is the first to report a close relationship between UCP4 deletion with PCs impairment, and suggests the importance of UCP4 in the substantial support of mitochondrial function homeostasis in bradykinesia. UCP4 might be a therapeutic target for the cerebela-related movement disorder.