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

Yeming Yang,Zhilin Jiang,Kuanxiang Sun,Wenjing Liu,Shujin Li,Fang Lu,Shanshan Zhang,Xianjun Zhu,Mu Yang,Kun Peng,Lin Zhang

doi:10.1038/s41419-018-0938-6

Abstract

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.

Highlights

Phospholipids are asymmetrically and dynamically distributed across plasma membranes[1,2]
Sections of cerebellum were immunostained with a specific antibody against transmembrane protein 30 A (TMEM30A), and PKC-γ served as a marker of the PCs46
Tmem30a is widely expressed in the cerebellum, in PKC-γ positive Purkinje cell (PC) as early as postnatal day 16 (P16) and in adulthood (Fig. S1)

Summary

Introduction

Phospholipids are asymmetrically and dynamically distributed across plasma membranes[1,2]. Mounting evidence indicates that the asymmetric distribution of lipids is largely determined by P4-ATPases, a diverse group of lipid transporters that use the energy of ATP hydrolysis to move specific lipids from the outer to the inner leaflet of. P4-ATPases generate and maintain the phospholipids asymmetry, which plays crucial roles in membrane stability, vesicle trafficking, blood coagulation, cell polarity and migration, clearance of apoptotic cells, cell division, sperm capacitation, and cell signaling[8,9,10,11,12,13]. Plasma membrane and endosomal system that play critical roles in vesicle formation and trafficking[14]. Drs[2] is essential for bidirectional vesicular transport between the TGN and early endosomes[9]. In Arabidopsis thaliana, ALA3 is required for the formation of post-

Methods

Results

Conclusion