TMEM106B — Transmembrane Protein 106B

TMEM106B — Transmembrane Protein 106B

Pathway Diagram

```mermaid
flowchart TD
TMEM106B["TMEM106B<br/>Gene"]

EndoLyso["Endosome-Lysosome<br/>Function"]
CellProp["Cell Subtype<br/>Proportion"]

Alzheimer["Alzheimer's<br/>Disease"]
ALS["Amyotrophic Lateral<br/>Sclerosis"]
Parkinson["Parkinson's<br/>Disease"]
FTD["Frontotemporal<br/>Dementia"]
Dementia["Dementia"]
MS["Multiple<br/>Sclerosis"]

Neurodegeneration["Neurodegeneration"]
Aging["Aging"]

TherapyAD["AD Therapeutic<br/>Target"]
TherapyALS["ALS Therapeutic<br/>Target"]
TherapyDem["Dementia Therapeutic<br/>Target"]
TherapyMS["MS Therapeutic<br/>Target"]

TMEM106B -->|"regulates"| EndoLyso
TMEM106B -->|"regulates"| CellProp

TMEM106B -->|"causes"| Alzheimer
TMEM106B -->|"causes"| ALS
TMEM106B -->|"causes"| Parkinson
TMEM106B -->|"causes"| FTD
TMEM106B -->|"causes"| Dementia

TMEM106B -->|"associated with"| Aging
TMEM106B -->|"causes"| Neurodegeneration

TMEM106B -.->|"therapeutic target"| TherapyAD
TMEM106B -.->|"therapeutic target"| TherapyALS
TMEM106B -.->|"therapeutic target"| TherapyDem
TMEM106B -.->|"therapeutic target"| TherapyMS

style TMEM106B fill:#006494
style EndoLyso fill:#ef5350
style CellProp fill:#4a1a6b
style Alzheimer fill:#5d4400
style ALS fill:#5d4400
style Parkinson fill:#5d4400
style FTD fill:#5d4400
style Dementia fill:#5d4400
style MS fill:#5d4400
style Neurodegeneration fill:#ef5350
style Aging fill:#5

TMEM106B — Transmembrane Protein 106B

Pathway Diagram

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TMEM106B — Transmembrane Protein 106B</th>
</tr>
<tr> [@brady2016]
<td class="label">Symbol</td> [@cruchaga2011]
<td><strong>TMEM106B</strong></td> [@van2014]
</tr> [@dolan2024]
<tr> [@nelson2015]
<td class="label">Full Name</td> [@feng2023]
<td>Transmembrane Protein 106B</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>7p21.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54664" target="_blank">54664</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000106460" target="_blank">ENSG00000106460</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/613413" target="_blank">613413</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NUM4" target="_blank">Q9NUM4</a></td>
</tr>
<tr>
<td class="label">Protein</td>
<td>TMEM106B (274 aa, type II TM lysosomal protein)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[FTD](/diseases/ftd) (risk factor), FTLD-TDP, LATE, Hippocampal sclerosis</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Cortex](/brain-regions/cortex), [Hippocampus](/brain-regions/hippocampus) (neurons, oligodendrocytes)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Variants</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">rs1990622 (sentinel SNP)<br>rs3173615 / p.T185S (functional)<br>Risk allele increases TMEM106B protein levels</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">164 edges</a></td>
</tr>
</table>

TMEM106B — Transmembrane Protein 106B

Introduction

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.

Overview

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](/proteins/tdp-43) inclusions (FTLD-TDP) through a genome-wide association study.[@van2010] 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](/proteins/amyloid-beta), tau], and [alpha-synuclein](/proteins/alpha-synuclein).2,3,4</a>

TMEM106B plays critical roles in lysosomal biology, [progranulin](/proteins/progranulin) regulation, and myelin homeostasis, and serves as a genetic modifier of multiple neurodegenerative diseases including [FTD](/diseases/ftd), [ALS](/diseases/als), and limbic-predominant age-related [TDP-43](/proteins/tdp-43) encephalopathy (LATE).

Gene Structure and Protein

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](/entities/neurons) and oligodendrocytes in the central nervous system, where it localizes to lysosomal membranes.[@brady2016]

Normal Function

Lysosomal Biology

TMEM106B is a key regulator of lysosomal morphology, localization, acidification, and intracellular trafficking. Its functions include:

• Lysosomal pH regulation: Interacts with accessory proteins of the vacuolar ATPase (v-ATPase) to maintain acidic lysosomal pH; elevated TMEM106B reduces v-ATPase activity and impairs acidification[@brady2016]
• Lysosomal enzyme levels: Loss of TMEM106B causes reduction in multiple lysosomal enzymes
• Lysosomal positioning: Modulates the subcellular distribution of lysosomes

Progranulin Regulation

TMEM106B regulates [progranulin](/proteins/progranulin) (encoded by [GRN](/proteins/grn-protein) 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](/proteins/grn-protein)-mediated [FTD](/diseases/ftd).[@cruchaga2011]

Role as FTD Risk Gene

Discovery (2010 GWAS)

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.[@van2010]

Key SNPs:

• rs1990622 — sentinel SNP in the 3' UTR; minor C-allele is protective (OR = 0.61 in FTD-TDP)
• rs3173615 — nonsynonymous coding SNP at codon 185 (p.T185S), in perfect linkage disequilibrium with rs1990622, likely the functional variant
• The major (T) risk allele increases TMEM106B protein levels in brain with aging

Modifier of GRN and C9orf72 FTD

TMEM106B was identified as the first genetic modifier of disease penetrance in [C9orf72](/proteins/c9orf72-protein) expansion carriers and [GRN](/proteins/grn-protein) mutation carriers:

• Homozygosity for the protective C-allele protects [GRN](/proteins/grn-protein) carriers from developing FTD[@cruchaga2011]
• TMEM106B deletion in progranulin-deficient mice normalizes lysosomal protein levels and rescues behavioral abnormalities
• In [C9orf72](/proteins/c9orf72-protein) carriers, the protective genotype reduces FTD risk but not Motor Neuron Disease risk[@van2014]

2022 Discovery: TMEM106B Amyloid Filaments

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.

Role in TDP-43 Pathology

A 2024 Science Translational Medicine study showed that TMEM106B core deposition correlates with [TDP-43](/proteins/tdp-43) pathology severity and is increased in carriers of the FTD risk SNP. TMEM106B fibrils appear to "tip [TDP-43](/mechanisms/tdp-43-proteinopathy) dysfunction into overdrive" by impairing lysosomal function and further disrupting protein quality control in [neurons](/entities/neurons) already stressed by TDP-43 mislocalization.[@dolan2024]

Other Disease Associations

Hippocampal Sclerosis and LATE

TMEM106B variants are strongly associated with:

• Hippocampal sclerosis of aging (HS-Aging) — a pathologic TDP-43 encephalopathy affecting the [hippocampus](/brain-regions/hippocampus) in the oldest-old[@nelson2015]
• Limbic-predominant age-related TDP-43 encephalopathy (LATE) — an increasingly recognized condition that mimics [Alzheimer's disease](/diseases/alzheimers-disease)

Brain Aging and Myelin

The TMEM106B risk allele specifically increases fibril formation and alters myelin lipid homeostasis in the aging [hippocampus](/brain-regions/hippocampus), providing a mechanistic link between the genetic variant and age-dependent neurodegeneration.[@feng2023]

Alzheimer's Disease

TMEM106B rs1990622 has also been associated with [Alzheimer's disease](/diseases/alzheimers-disease) risk modification, though the effect size is smaller than for FTD.

Brain Atlas Resources

• [Allen Brain Atlas](https://brain-map.org)
• [Allen Human Brain Atlas: TMEM106B search](https://human.brain-map.org/microarray/search/show?search_term=TMEM106B)
• [Allen Mouse Brain Atlas: TMEM106B search](https://mouse.brain-map.org/search/index.html?query=TMEM106B)
• [Allen Cell Type Atlas](https://portal.brain-map.org/atlases-and-data/rnaseq)
• [BrainSpan Developmental Transcriptome](https://www.brainspan.org)

External Links

• [NCBI Gene: TMEM106B](https://www.ncbi.nlm.nih.gov/gene/54664)
• [OMIM: 613413](https://omim.org/entry/613413)
• [UniProt: Q9NUM4](https://www.uniprot.org/uniprot/Q9NUM4)
• [Allen Human Brain Atlas: TMEM106B](https://human.brain-map.org/microarray/search/show?search_term=TMEM106B)

See Also

• [alpha-synuclein](/proteins/alpha-synuclein)
• [progranulin](/proteins/progranulin)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Amyloid-Beta Aggregation](/mechanisms/amyloid-aggregation)
• [Tau Pathology](/mechanisms/tau-pathology)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [ALS](/diseases/als)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Hippocampus](/brain-regions/hippocampus)
• [Cerebral Cortex](/brain-regions/cortex)

Background

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.

References

Pathway Diagram

The following diagram shows the key molecular relationships involving TMEM106B — Transmembrane Protein 106B discovered through SciDEX knowledge graph analysis: