| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學系 === 104 === The spinocerebellar ataxias (SCA) are a diverse group of autosomal dominant neurological disorders characterized by progressive degeneration of many nevrse systems, including cerebellum, spinocerebellar tracts, and brain stem neurons. Recent discovery of mutations in the voltage-gated potassium channel Kv4.3-encoded gene KCND3 has shown to be the cause of the autosomal dominant spinocerebellar ataxia type 22 (SCA22). Of all KCND3 mutations, the in-frame three-nucleotide deletion c.679_681delTTC p.F227del (KCND3-ΔF227) has been identified in either the French and Chinese pedigrees. The in-frame point mutation c.1304G>T p.G345V (KCND3-G345V) has been identified in either the American and Japanese pedigrees. Since the underlying pathomechanisms of SCA22 is poorly understood, we generate Drosophila models for SCA22 by overexpression of wild-type KCND3, and mutant KCND3 variants (i.e. ΔF227; G345V) using the UAS/Gal4 system to address the above question. Ectopic expression of mutant KCND3 cause various pathological features, including neurodegeneration, apoptosis, mobility defects and shortened lifespan. More detailed analysis of mRNA and protein expression level found that ΔF227 translation abnormally by decreases in protein production. Since immunocytochemistry analyses revealed that KCND3-ΔF227 retained in the endoplasmic reticulum (ER). We suspect that KCND3-ΔF227 might induces ER stress thereby inducing neurodegenerations. Additionally, KCND3 is a potassium channel, ectopic KCND3 expression may cause the imbalance intracellular potassium concentration and lead to neuronal cell death. All the above mentioned possible pathomechanisms will be investigated with the newly established models.
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