Abstract
BackgroundTransmembrane protein 106B (TMEM106B) has been identified as a risk factor for frontotemporal lobar degeneration, which is the second most common form of progressive dementia in people under 65 years of age. Mutations in charged multivesicular body protein 2B (CHMP2B), which is involved in endosomal protein trafficking, have been found in chromosome 3-linked frontotemporal dementia. Despite the number of studies on both CHMP2B and TMEM106B in the endolysosomal pathway, little is known about the relationship between CHMP2B and TMEM106B in the endosomal/autophagy pathway.ResultsThis study found that endogenous TMEM106B was partially sequestered in CHMP2B-positive structures, suggesting its possible involvement in endosomal sorting complexes required for transport (ESCRT)-associated pathways. The role of single nucleotide polymorphisms of TMEM106B (T185, S185, or S134N) in the ESCRT-associated pathways were characterized. The T185 and S185 variants were more localized to Rab5-/Rab7-positive endosomes compared with S134N, while all of the variants were more localized to Rab7-positive endosomes compared to Rab5-positive endosomes. T185 was more associated with CHMP2B compared to S185. Autophagic flux was slightly reduced in the T185-expressing cells compared to the control or S185-expressing cells. Moreover, T185 slightly enhanced the accumulation of EGFR, impairments in autophagic flux, and neurotoxicity that were caused by CHMP2BIntron5 compared to S185-expressing cells.ConclusionsThese findings suggest that the T185 variant functions as a risk factor in neurodegeneration with endolysosomal defects. This study provides a better understanding of pathogenic functions of TMEM106B, which is a risk factor for the progression of neurodegenerative diseases that are associated with endosomal defects in the aged brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0177-z) contains supplementary material, which is available to authorized users.
Highlights
Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative disease, after Alzheimer’s disease and Parkinson’s disease [1]
Localization of endogenous TMEM106B to CHMP2BWT- or CHMP2BIntron5-positive structures in cultured cortical neurons In order to determine whether TMEM106B was involved in the endosomal sorting complexes required for transport (ESCRT)-associated endosomal pathway, we first examined the cellular localization of TMEM106B in CHMP2BWT- and CHMP2BIntron5-expressing cortical neurons [23]
Some TMEM106B-positive particles were adjacent to charged multivesicular body protein 2B (CHMP2B)-positive structures, which indicated its possible association with the ESCRT complex in the endosomal pathway
Summary
Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative disease, after Alzheimer’s disease and Parkinson’s disease [1]. Linkage disequilibrium studies have shown that the top three singlenucleotide polymorphisms (SNPs) (rs6966915, rs1020004, and rs1990622) in the noncoding region of TMEM106B are associated with FTLD-TDP, and TMEM106B mRNA and protein expression are significantly increased in the frontal cortex of patients with FTLD-TDP compared with controls, suggesting its importance in normal brain function [9]. TMEM106B has been shown to be a genetic modifier in patients with FTLD with C9ORF72 expansions, which are the most common known genetic cause of frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and the combination of these diseases [4, 11]. Transmembrane protein 106B (TMEM106B) has been identified as a risk factor for frontotemporal lobar degeneration, which is the second most common form of progressive dementia in people under 65 years of age. Despite the number of studies on both CHMP2B and TMEM106B in the endolysosomal pathway, little is known about the relationship between CHMP2B and TMEM106B in the endosomal/autophagy pathway
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