| TMEM106B | |
|---|---|
| Gene | [TMEM106B](/genes/tmem106b) |
| UniProt | Q9NUM4 |
| PDB | N/A |
| Mol. Weight | 31 kDa |
| Localization | Late endosomes and lysosomes |
| Family | Type II lysosomal transmembrane protein family |
| Diseases | [Frontotemporal Dementia](/diseases/ftd), [ALS](/diseases/als), [LATE](/diseases/late-encephalopathy) |
TMEM106B (Transmembrane Protein 106B) is a 323-amino acid type II lysosomal transmembrane protein encoded by the TMEM106B gene on chromosome 7p21.1. Originally identified as a genetic risk factor for frontotemporal lobar degeneration (FTLD) through genome-wide association studies, TMEM106B has emerged as a critical regulator of lysosomal function with implications for multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis [1].
The TMEM106B gene spans approximately 17 kb and consists of 9 exons. The protein localizes primarily to the membrane of late endosomes and lysosomes, where it exists as a homodimer. Structural studies indicate that TMEM106B contains a short N-terminal cytoplasmic domain (approximately 10 amino acids), a single transmembrane helix, and a large C-terminal luminal domain that faces the interior of lysosomes [2].
The TMEM106B protein exhibits several distinctive features:
TMEM106B functions as a master regulator of lysosomal function, affecting multiple aspects of lysosomal biology that are critical for neuronal health [3]:
Proper lysosomal function requires an acidic interior (pH 4.5-5.0) maintained by v-type ATPases. TMEM106B contributes to:
TMEM106B influences endosomal-lysosomal trafficking through:
A critical function of TMEM106B is its role in autophagy, the cellular recycling system that degrades damaged organelles and protein aggregates:
The TMEM106B locus was first identified as a major risk factor for FTLD in a landmark genome-wide association study that identified the single nucleotide polymorphism (SNP) rs1990620 on chromosome 7p21 [1:1]. This finding has been replicated in multiple independent cohorts and expanded to include:
The amino acid substitution threonine to serine at position 185 (T185S) represents the most functionally significant TMEM106B variant:
| Allele | Effect | Frequency (European) | Disease Association |
|---|---|---|---|
| T185 (protective) | Higher TMEM106B expression | ~40% | Reduced FTLD risk |
| S185 (risk) | Lower TMEM106B expression | ~60% | Increased FTLD risk, especially with GRN mutations |
TMEM106B acts as a powerful modifier of several monogenic neurodegenerative conditions:
TMEM106B strongly modifies disease onset and phenotype in individuals with GRN mutations:
The hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of FTLD/ALS. TMEM106B risk variants:
A central finding in TMEM106B biology is its relationship with TDP-43 proteinopathy, the characteristic pathological hallmark of most FTLD subtypes and ALS [6]:
TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA-binding protein that:
Understanding the TMEM106B-TDP-43 relationship has opened several therapeutic avenues:
TMEM106B and progranulin have a complex genetic and functional relationship [7]:
Mutations in CHMP2B cause a rare form of FTLD (FTD-3). TMEM106B associates with CHMP2B as part of the ESCRT-III complex involved in membrane remodeling [8].
Emerging evidence links TMEM106B to Alzheimer's disease pathology:
TMEM106B is highly expressed in neurons where it:
Microglial TMEM106B affects:
Myelinating oligodendrocytes require TMEM106B for:
TMEM106B has significant potential as a biomarker for neurodegenerative disease:
Emerging evidence links TMEM106B to Parkinson's disease:
TMEM106B expression changes with age:
Van Deerlin VM et al. (2010). "Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions." Nat Genet 42: 234-239. Van Deerlin VM et al. 2010. ↩︎ ↩︎
UniProt (n.d.). TMEM106B - Q9NUM4. UniProt. ↩︎
Van Meensel J et al. (2019). "TMEM106B: a master regulator of lysosomal function?" Autophagy 15: 1072-1073. Van Meensel J et al. 2019. ↩︎
Schwenk BM et al. (2014). "TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers." Brain 137: 2653-2659. Schwenk BM et al. 2014. ↩︎
Chen-Plotkin AS et al. (2024). "TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal lobar degeneration." Sci Transl Med 16: eabf9735. Chen-Plotkin AS et al. 2024. ↩︎ ↩︎
Finch N et al. (2011). "TMEM106B risk variant is associated with TDP-43 pathology in aged brain." Acta Neuropathol 122: 619-622. Finch N et al. 2011. ↩︎
Brett SE et al. (2022). "The lysosomal protein TMEM106B interacts with GRN and regulates lysosomal function." Cell Rep 40: 111107. Brett SE et al. 2022. ↩︎
Luo L et al. (2015). "TMEM106B, a frontotemporal lobar dementia modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III." Mol Brain 8: 85. Luo L et al. 2015. ↩︎
Nichols N et al. (2015). "TMEM106B effects on cortical structure in FTLD and AD." Neurology 85: 1534-1541. Nichols N et al. 2015. ↩︎
Lynch C et al. (2019). "TMEM106B Effect on cognition in Parkinson disease and Frontotemporal Dementia." Ann Neurol 86: 439-451. Lynch C et al. 2019. ↩︎