Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

• Published in: Cell death & disease Vol. 9; no. 9; pp. 899 - 13
• Main Authors: Yang, Yeming, Sun, Kuanxiang, Liu, Wenjing, Zhang, Lin, Peng, Kun, Zhang, Shanshan, Li, Shujin, Yang, Mu, Jiang, Zhilin, Lu, Fang, Zhu, Xianjun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-09-2018; Springer Nature B.V
• Subjects: 14/63; 38; 38/77; 45; 45/41; 64; 64/110; 64/60; 82/29; 82/80; Age; Antibodies; Apoptosis; Ataxia; Biochemistry; Biomedical and Life Sciences; CCAAT/enhancer-binding protein; Cell Biology; Cell Culture; Cell death; Central nervous system; Cerebellar ataxia; Cerebellum; Degeneration; Dendritic spines; DNA nucleotidylexotransferase; Endoplasmic reticulum; Glial fibrillary acidic protein; Gliosis; Immunology; Life Sciences; Phosphatidylethanolamine; Phosphatidylserine; Phospholipids; Protein folding; Protein transport; Proteins; Purkinje cells
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0938-6

Phospholipids are asymmetrically distributed across mammalian plasma membrane with phosphatidylserine (PS) and phosphatidylethanolamine concentrated in the cytoplasmic leaflet of the membrane bilayer. This asymmetric distribution is dependent on a group of P4-ATPases named PS flippases. The proper transport and function of PS flippases require a β-subunit transmembrane protein 30 A (TMEM30A). Disruption of PS flippases led to several human diseases. However, the roles of
TMEM30A
in the central nervous system remain elusive. To investigate the role of
Tmem30a
in the cerebellum, we developed a
Tmem30a
Purkinje cell (PC)-specific knockout (KO) mouse model. The
Tmem30a
KO mice displayed early-onset ataxia and progressive PC death. Deficiency in
Tmem30a
led to an increased expression of Glial fibrillary acidic protein and astrogliosis in regions with PC loss. Elevated C/EBP homologous protein and BiP expression levels indicated the presence of endoplasmic reticulum stress in the PCs prior to visible cell loss. Terminal deoxynucleotidyl transferase dUTP nick end labeling (
TUNEL
) analysis suggested that apoptotic cell death occurred in the cerebellum. Our data demonstrate that loss of
Tmem30a
in PCs results in protein folding and transport defects, a substantial decrease in dendritic spine density, increased astrogliosis and PC death. Taken together, our data demonstrate an essential role of
Tmem30a
in the cerebellum PCs.