TMEM106B expression is reduced in Alzheimer’s disease brains

Jun-Ichi Satoh,Yuko Saito,Yoshihiro Kino,Yoji Yamamoto,Natsuki Kawana,Kunimasa Arima,Tsuyoshi Ishida

doi:10.1186/alzrt247

Abstract

IntroductionTMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer’s disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown.MethodsBy quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy and non-neurological cases.ResultsIn AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN.ConclusionsWe found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD.

Highlights

TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/ lysosome compartments expressed ubiquitously in various cell types
TMEM106B is a type II transmembrane glycoprotein of unknown function located within the late endosome/lysosome compartments expressed ubiquitously in various cell types, where the levels of TMEM106B expression are regulated by lysosomal activities [7,8]
P.T185S genotyping The rs3173615 single nucleotide polymorphism (SNP) composed of p.T185S (C760G) in exon 6 of the human TMEM106B gene was studied by direct sequencing of a 226 bp product amplified from brain cDNA by polymerase chain reaction (PCR) using a primer set of 5′-cagcctatgtcagttatgatg-3′ and 5′-tctgctataacggtaggtact-3′

Summary

Introduction

TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/ lysosome compartments expressed ubiquitously in various cell types. The genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. The first international genome-wide association study of FTLD with ubiquitinated TAR DNA-binding protein-43-positive inclusions (FTLD-TDP) identified a significant association with three distinct single nucleotide polymorphisms (SNPs) numbered rs1020004, rs6966915, and rs1990622 (top SNP) in the transmembrane protein 106B (TMEM106B) gene on chromosome 7p21.3 [1]. TMEM106B is a type II transmembrane glycoprotein of unknown function located within the late endosome/lysosome compartments expressed ubiquitously in various cell types, where the levels of TMEM106B expression are regulated by lysosomal activities [7,8]. The frequency of carriers homozygous for S185 on rs3173615 is reduced in the patients with C9orf repeat expansions, the most common genetic cause for FTLD [15], whereas the risk T allele on rs1990622 is positively associated with later age at onset and death in C9orf repeat expansion carriers [16]

Methods

Results

Discussion

Conclusion