TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III

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.

What we know about TMEM106B in neurodegeneration

“…These protein interactions together with TMEM106B’s endolysosomal localization would imply that the TMEM106B cytoplasmic domain possibly participates in the delivery of endocytic cargos to the lysosome. In agreement with this hypothesis, Jun and colleagues reported that TMEM106B also directly binds to CHMP2B [35], known to be a member of the endosomal sorting complexes required for transport III (ESCRT-III) complex that regulates endolysosomal protein trafficking and autophagic structure formation [27, 28]. One additional report identified the C-terminus of microtubule-associated protein 6 (Map6) to also directly bind the N-terminus of Tmem106b by utilizing mass spectrometry analysis of rat brain Tmem106b immunoprecipitation samples [66].…”

“…Nonetheless, one feature found in patients with disease-causing CHMP2B mutations is the presence of large vacuolar structures in the brain that label positive for endosomal proteins, suggesting an endosomal-related disease mechanism [31]. Interestingly, Jun and colleagues found endogenous Tmem106b to partially co-localize to both wild-type CHMP2B- and mutant CHMP2B-positive structures in mouse neurons [35], further highlighting a potential role for TMEM106B in the endolysosomal pathway. Moreover, this study showed that T185 TMEM106B more readily binds to CHMP2B than S185 TMEM106B, and that T185 TMEM106B-CHMP2B binding is enhanced with the mutant form of CHMP2B [35].…”

“…Interestingly, Jun and colleagues found endogenous Tmem106b to partially co-localize to both wild-type CHMP2B- and mutant CHMP2B-positive structures in mouse neurons [35], further highlighting a potential role for TMEM106B in the endolysosomal pathway. Moreover, this study showed that T185 TMEM106B more readily binds to CHMP2B than S185 TMEM106B, and that T185 TMEM106B-CHMP2B binding is enhanced with the mutant form of CHMP2B [35]. Also, overexpression of T185 TMEM106B showed a greater reduction in autophagic flux, commonly used to measure autophagic degradation activity, versus the S185 variant of TMEM106B, and this difference was independent of total TMEM106B levels [35].…”

“…Moreover, this study showed that T185 TMEM106B more readily binds to CHMP2B than S185 TMEM106B, and that T185 TMEM106B-CHMP2B binding is enhanced with the mutant form of CHMP2B [35]. Also, overexpression of T185 TMEM106B showed a greater reduction in autophagic flux, commonly used to measure autophagic degradation activity, versus the S185 variant of TMEM106B, and this difference was independent of total TMEM106B levels [35]. Whether these CHMP2B-related differences in TMEM106B variants contribute to the observed associations in all forms of FTLD-TDP remains to be determined.…”

The role of nuclear PKMζ in memory maintenance

“…Co-immunoprecipitation and western blotting were performed as previously described (Jun et al, 2015; Kim et al, 2014). Briefly, HEK293T cells were transfected with a 3XFLAG-PKMζ (interaction between PKMζ and importin) or 3XFLAG-CBP and pCMV-PKMζ (interaction between PKMζ and CBP) expression plasmid.…”