| TMEM106B — Transmembrane Protein 106B | |
|---|---|
| Symbol | TMEM106B |
| Full Name | Transmembrane Protein 106B |
| Chromosome | 7p21.3 |
| NCBI Gene | 54664 |
| Ensembl | ENSG00000106460 |
| OMIM | 613413 |
| UniProt | Q9NUM4 |
| Protein | TMEM106B (274 aa, type II TM lysosomal protein) |
| Diseases | FTD (risk factor), FTLD-TDP, LATE, Hippocampal sclerosis |
| Expression | Cortex, Hippocampus (neurons, oligodendrocytes) |
| Key Variants | |
| rs1990622 (sentinel SNP) rs3173615 / p.T185S (functional) Risk allele increases TMEM106B protein levels |
|
Tmem106B — Transmembrane Protein 106B is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
TMEM106B (Transmembrane Protein 106B) is a gene on chromosome 7p21.3 encoding a 274-amino acid type II transmembrane lysosomal protein. TMEM106B was identified in 2010 as the number-one genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through a genome-wide association study.[1] In a transformative 2022 discovery, four independent research groups revealed that the C-terminal fragment of TMEM106B forms amyloid filaments in aged human brains — establishing a new category of age-related brain amyloid distinct from amyloid-beta, tau], and alpha-synuclein.2,3,4
TMEM106B plays critical roles in lysosomal biology, progranulin regulation, and myelin homeostasis, and serves as a genetic modifier of multiple neurodegenerative diseases including FTD, ALS, and limbic-predominant age-related TDP-43 encephalopathy (LATE).
TMEM106B spans approximately 32 kb on chromosome 7p21.3 and contains 9 exons. The encoded protein is a 274-amino acid type II transmembrane protein with a short N-terminal cytoplasmic tail, a single transmembrane domain, and a large luminal C-terminal domain (residues 120-254) that resides within the lysosomal lumen. It is primarily expressed in neurons and oligodendrocytes in the central nervous system, where it localizes to lysosomal membranes.[5]
TMEM106B is a key regulator of lysosomal morphology, localization, acidification, and intracellular trafficking. Its functions include:
TMEM106B regulates progranulin (encoded by GRN protein levels — progranulin is a lysosomal growth factor critical for neuronal survival. The TMEM106B risk allele increases TMEM106B protein with aging, which in turn modulates progranulin processing and lysosomal function. This functional interaction explains why TMEM106B is such a strong modifier of GRN-mediated FTD.[6]
In 2010, Van Deerlin and colleagues published the landmark GWAS analyzing 515 pathologically confirmed FTLD-TDP cases and 2,509 controls. They identified 3 SNPs in a 68-kb region on chromosome 7p21.3 associated with FTLD-TDP at genome-wide significance, with the top marker rs1990622 reaching p = 1.08 x 10^-11.[1]
Key SNPs:
TMEM106B was identified as the first genetic modifier of disease penetrance in C9orf72 expansion carriers and GRN mutation carriers:
Four independent research groups published simultaneous papers in 2022 using cryo-EM that fundamentally changed understanding of this protein:
Key finding: TMEM106B fibrils represent a new type of age-related brain amyloid, present in cognitively normal individuals over age 50 and dramatically increased in neurodegenerative disease brains. This was one of the most surprising structural biology discoveries in neurodegeneration research.
A 2024 Science Translational Medicine study showed that TMEM106B core deposition correlates with TDP-43 pathology severity and is increased in carriers of the FTD risk SNP. TMEM106B fibrils appear to "tip TDP-43 dysfunction into overdrive" by impairing [lysosomal] function and further disrupting protein quality control in neurons already stressed by TDP-43 mislocalization.[8]
TMEM106B variants are strongly associated with:
The TMEM106B risk allele specifically increases fibril formation and alters myelin lipid homeostasis in the aging hippocampus, providing a mechanistic link between the genetic variant and age-dependent neurodegeneration.[10]
TMEM106B rs1990622 has also been associated with Alzheimer's disease risk modification, though the effect size is smaller than for FTD.
The study of Tmem106B — Transmembrane Protein 106B has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.