The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

Hiroaki Suzuki,Masaaki Matsuoka

doi:10.1074/jbc.m116.737171

Hiroaki Suzuki, Masaaki Matsuoka

Open Access

https://doi.org/10.1074/jbc.m116.737171

Copy DOI

Abstract

A common genetic variation in the transmembrane protein 106B (TMEM106B) gene has been suggested to be a risk factor for frontotemporal lobar degeneration (FTLD) with inclusions of transactive response DNA-binding protein-43 (TDP-43) (FTLD-TDP), the most common pathological subtype in FTLD. Furthermore, previous studies have shown that TMEM106B levels are up-regulated in the brains of FTLD-TDP patients, although the significance of this finding remains unknown. In this study, we show that the overexpression of TMEM106B and its N-terminal fragments induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of TDP-43, which represents TDP-43 pathology, using cell-based models. TMEM106B-induced death is mediated by the caspase-dependent mitochondrial cell death pathways and possibly by the lysosomal cell death pathway. These findings suggest that the up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP.

Highlights

We show that the overexpression of TMEM106B induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of transactive response DNA-binding protein-43 (TDP-43), a representative TDP-43 pathology observed in frontotemporal lobar degeneration (FTLD)-TDP, using cell-based models
At 24 h after the start of infection, media were replaced with DMEM/N2 supplement
At 48 h after the start of transfection, media were replaced with DMEM/N2 supplement containing (ϩ) or not containing (Ϫ) 0.05 ␮M staurosporine

Summary

Introduction

Treatment of the cells overexpressing TMEM106B-FL with lysosomal protease inhibitors leupeptin, pepstatin A, and E-64d partially inhibited the generation of NTF17 (Fig. 2D, cf lanes 2 and 3–5). Overexpression of TMEM106B Induces Cell Death—It has been reported that levels of TMEM106B are up-regulated in the brains of FTLD-TDP patients, especially in those with GRN mutations [11, 13, 20, 23]. The overexpression of TMEM106B(1–127) and TMEM106B(1–106) induced cell death in an expression level-dependent manner (Fig. 5A).

Results

Conclusion