Physiological analysis of Nna1 using the conditional knock out method

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H06812
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Niigata University
• Principal Investigator: ZHOU LI 新潟大学, 医歯学総合研究科, 特任助教 (80568410)
• Research Collaborator: Sakimura kenji
• Project Period (FY): 2016-08-26 – 2018-03-31
• Keywords: Nna1 / Purkinje cell / knock out / apoptosis / ataxia / craboxypeptidase domain

Outline of Final Research Achievements

Purkinje cell degeneration (pcd) mutant mouse was first identified as a spontaneous mutation showing ataxic behavior in an autosomal recessive manner. The causative gene is Nna1. To test whether the carboxypeptidase domain of Nna1 is essentia, we generated a conditional allele of Nna1, in which carboxypeptidase domain-encoding exon 21 and 22 are floxed to generate null knockout (KO) mice. Nna1 KO mice showed obvious ataxia with smaller body size than WT. Rotarod test showed dysfunction in motor coordination and disability in motor learning. Cerebellar atrophy, purkinje cell (PC) loss and dendrite disappearance were observed in the cerebellum of Nna1 KO mice. Apoptotic cells were detected not only in the PC layer, but also in the molecular layer and the granule cell layer. Our datas indicate that loss-of-function of Nna1 results in the pcd phenotypes and that cell death occur not only in Purkinje cells but in other cell types in the cerebellum and other organs as testis and retina.

Free Research Field

神経生物学

Academic Significance and Societal Importance of the Research Achievements

特定遺伝子Nna1の異常による小脳の機能障害はマウスだけではなく、人間の病気にも指摘されている。ちなみに、最近の臨床研究より、Nna1遺伝子の異常は、知能障害、歩行障害という小脳の病気が報告されている。Nna1 KOマウスを用いて、その病態を解明し、治療法の検討と薬物の開発に活かせばよいと考えられる。今後、症状を緩和する目標として、Nna1 KOマウスに対する治療方法への探索を行っていく予定である。