TMEM106B Protein (Transmembrane Protein 106B)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">TMEM106B Protein (Transmembrane Protein 106B)</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Antisense Oligonucleotides</td>
<td>Reduce TMEM106B expression</td>
</tr>
<tr>
<td class="label">Small Molecule Inhibitors</td>
<td>Block fibril formation</td>
</tr>
<tr>
<td class="label">Antibodies</td>
<td>Target fibrillar TMEM106B</td>
</tr>
<tr>
<td class="label">Lysosomal Enhancers</td>
<td>Boost lysosomal function downstream</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Type</td>
</tr>
<tr>
<td class="label">V-ATPase</td>
<td>Complex</td>
</tr>
<tr>
<td class="label">Dynein/Dynactin</td>
<td>Motor</td>
</tr>
<tr>
<td class="label">GRN</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">TDP-43</td>
<td>Pathology</td>
</tr>
<tr>
<td class="label">α-Synuclein</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Cathepsins</td>
<td>Enzymes</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" styl
...TMEM106B Protein (Transmembrane Protein 106B)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">TMEM106B Protein (Transmembrane Protein 106B)</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Antisense Oligonucleotides</td>
<td>Reduce TMEM106B expression</td>
</tr>
<tr>
<td class="label">Small Molecule Inhibitors</td>
<td>Block fibril formation</td>
</tr>
<tr>
<td class="label">Antibodies</td>
<td>Target fibrillar TMEM106B</td>
</tr>
<tr>
<td class="label">Lysosomal Enhancers</td>
<td>Boost lysosomal function downstream</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Type</td>
</tr>
<tr>
<td class="label">V-ATPase</td>
<td>Complex</td>
</tr>
<tr>
<td class="label">Dynein/Dynactin</td>
<td>Motor</td>
</tr>
<tr>
<td class="label">GRN</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">TDP-43</td>
<td>Pathology</td>
</tr>
<tr>
<td class="label">α-Synuclein</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Cathepsins</td>
<td>Enzymes</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>
<div style="float: right; width: 280px; background: #f8f9fa; padding: 12px; border: 1px solid #ddd; border-radius: 4px; margin: 0 0 1em 1em; font-size: 0.9em;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">TMEM106B Protein</h3>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px 0;"><strong>Symbol:</strong></td><td>TMEM106B</td></tr>
<tr><td style="padding: 4px 0;"><strong>Also known as:</strong></td><td>Transmembrane Protein 106B</td></tr>
<tr><td style="padding: 4px 0;"><strong>UniProt:</strong></td><td>[Q9NUM4](https://www.uniprot.org/uniprot/Q9NUM4)</td></tr>
<tr><td style="padding: 4px 0;"><strong>Gene:</strong></td><td>[TMEM106B](/genes/tmem106b)</td></tr>
<tr><td style="padding: 4px 0;"><strong>MW:</strong></td><td>30.3 kDa</td></tr>
<tr><td style="padding: 4px 0;"><strong>Location:</strong></td><td>Lysosomal membrane</td></tr>
<tr><td style="padding: 4px 0;"><strong>PDB:</strong></td><td>[7S7P](https://www.rcsb.org/structure/7S7P), [7Q5B](https://www.rcsb.org/structure/7Q5B)</td></tr>
</table>
</div>
Pathway Diagram
Mermaid diagram (expand to render)
Knowledge graph relationships for TMEM106B (293 total edges in KG)
Overview
TMEM106B (Transmembrane Protein 106B) is a lysosomal membrane protein that has emerged as a major genetic risk factor for frontotemporal dementia (FTD) and Parkinson's disease (PD). First identified through genome-wide association studies (GWAS) in 2010, TMEM106B variants modulate disease risk, age of onset, and pathology in multiple neurodegenerative conditions[@van2010][@chang2022].
Recent cryo-EM studies have revealed that TMEM106B forms fibrillar aggregates in the brains of aged individuals and those with neurodegenerative diseases, redefining our understanding of this protein and opening new avenues for therapeutic intervention[@schweighauser2022].
Structure and Domain Architecture
TMEM106B is a 274-amino acid type II transmembrane protein:
N-terminal Cytoplasmic Domain (residues 1-92):
- Contains multiple lysosomal targeting motifs
- Includes the critical D252 residue where pathogenic variants occur
- Subject to proteolytic cleavage
Transmembrane Domain (residues 93-113):
- Single α-helix anchoring the protein to the lysosomal membrane
- Orientation: N-terminus cytoplasmic, C-terminus luminal
Luminal C-terminal Domain (residues 114-274):
- Lumenal domain with glycosylation sites
- Contains the core amyloidogenic region (residues 120-254)
- Forms the fibril core in pathological aggregates[@cao2022]
Fibril Structure
Cryo-EM structures reveal that TMEM106B forms amyloid-like fibrils with:
- Single protofilament architecture
- Residues 120-254 forming the structured fibril core
- Multiple polymorphic fibril structures identified
- Post-translational modifications affect fibril formation[@jiang2022]
Normal Function
Lysosomal Biology
TMEM106B plays key roles in lysosomal function:
Lysosomal Trafficking: Regulates lysosomal positioning and motility within [neurons](/entities/neurons)[@schwenk2014].
Lysosomal Size: TMEM106B deficiency leads to enlarged lysosomes with abnormal morphology.
Lysosomal Acidification: Modulates lysosomal pH through effects on V-ATPase function[@busa2021].
Lysosomal Enzyme Activity: Affects activity of multiple lysosomal hydrolases including cathepsins.Neuronal Function
In neurons, TMEM106B contributes to:
Axonal Transport: Regulates lysosomal movement along axons via interactions with the motor protein complex.
Dendritic Morphology: Influences dendritic branching and spine density.
[Autophagy](/entities/autophagy): Modulates autophagosome-lysosome fusion and autophagic flux[@brady2013].
Protein Degradation: Facilitates clearance of misfolded and aggregated proteins.Role in Neurodegeneration
Frontotemporal Dementia
TMEM106B is a major genetic modifier in FTD:
GRN Mutation Carriers: The TMEM106B rs1990622 variant dramatically affects disease presentation in progranulin (GRN) mutation carriers:
- Protective allele delays onset by ~13 years
- Risk allele accelerates onset by ~7 years[@finch2011]
[C9orf72](/entities/c9orf72) Expansion: TMEM106B variants modify penetrance and phenotype in C9orf72 carriers.
Pathology Correlation: TMEM106B genotype correlates with [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology burden and distribution.
Mechanism: TMEM106B may affect lysosomal degradation of TDP-43 and other disease proteins[@chenplotkin2012].Parkinson's Disease
TMEM106B is a confirmed PD risk gene:
GWAS Significance: Multiple studies identify TMEM106B as a PD susceptibility locus.
Age of Onset: TMEM106B variants influence PD age of onset and progression[@nalls2014].
[α-Synuclein](/proteins/alpha-synuclein) Pathology: TMEM106B affects lysosomal degradation of α-synuclein.
GBA Interaction: Potential interaction between TMEM106B and GBA variants in PD risk.TMEM106B Fibril Pathology
A landmark discovery in 2022 revealed TMEM106B forms fibrils:
Prevalence: TMEM106B fibrils found in:
- ~75% of individuals over 80 years
- Nearly 100% of FTD cases
- Most LATE (limbic-predominant age-related TDP-43 encephalopathy) cases[@nelson2022]
Distribution: Fibrils accumulate in:
- Neuronal cell bodies and processes
- Glial cells
- Blood vessel walls
Co-aggregation: TMEM106B fibrils often co-localize with:
- TDP-43 inclusions
- [Tau](/proteins/tau) tangles
- α-Synuclein aggregates[@suarezcalvet2020]
Pathological Significance: Debate continues whether TMEM106B fibrils are:
- Pathogenic aggregates causing dysfunction
- Protective structures sequestering misfolded proteins
- Epiphenomena of lysosomal stress
LATE Syndrome
TMEM106B fibrils are particularly abundant in LATE:
Definition: LATE is defined by TDP-43 pathology in older adults mimicking Alzheimer's.
TMEM106B Role: The protein's fibrils may contribute to TDP-43 mislocalization and aggregation.
Risk Factor: TMEM106B variants are the strongest genetic risk factors for LATE[@nelson2019].Therapeutic Targeting
Current Strategies
No TMEM106B-targeted therapies are approved, but several approaches are under investigation:
Challenges
Loss-of-Function Concerns: TMEM106B has important physiological functions; complete inhibition may be harmful.
Fibril Pathogenicity: Unclear whether fibrils should be targeted or represent a protective response[@ludtmann2019].
[Blood-Brain Barrier](/entities/blood-brain-barrier): Antibodies and larger molecules require CNS delivery strategies.
Isoform Specificity: Need to understand effects of different TMEM106B variants.Key Interactions
See Also
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [TDP-43 Protein](/proteins/tdp43)
- [Progranulin](/proteins/grn)
- [Lysosomal Function](/mechanisms/lysosomal-function)
- [LATE](/diseases/late)
References
[Van Deerlin VM, Sleiman PM, Martinez-Lage M, et al, Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions (2010)](https://doi.org/10.1038/ng.536)
[Chang A, Xiang X, Wang J, et al, Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases (2022)](https://doi.org/10.1016/j.cell.2022.02.026)
[Schweighauser M, Arseni D, Bacioglu M, et al, Age-dependent emergence of TMEM106B fibrils in human brains (2022)](https://doi.org/10.1038/s41586-022-04650-z)
[Cao Q, Boyer DR, Park J, et al, Cryo-EM structures of four polymorphic TMEM106B fibrils (2022)](https://doi.org/10.1038/s41594-022-00814-8)
[Jiang YX, Cao Q, Sawaya MR, et al, Amyloid fibrils in FTLD-TDP are composed of TMEM106B (2022)](https://doi.org/10.1038/s41586-022-04670-9)
[Schwenk BM, Lang CM, Hogl S, et al, The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes (2014)](https://doi.org/10.1002/embj.201385857)
[Busa T, Parc AL, Broussolle E, et al, TMEM106B regulates lysosomal function and neuronal vulnerability to oxidative stress (2021)](https://doi.org/10.1523/JNEUROSCI.0743-21.2021)
[Brady OA, Zheng Y, Murphy K, et al, The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function (2013)](https://doi.org/10.1093/hmg/dds475)
[Finch N, Carrasquillo MM, Baker M, et al, TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers (2011)](https://doi.org/10.1212/WNL.0b013e31820a0e93)
[Chen-Plotkin AS, Unger TL, Gallagher MD, et al, TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA miR-132/212 cluster in brain (2012)](https://doi.org/10.1093/hmg/dds222)
[Nalls MA, Pankratz N, Lill CM, et al, Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease (2014)](https://doi.org/10.1038/ng.3043)
[Nelson PT, Brayne C, Flanagan ME, et al, Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology (2022)](https://doi.org/10.1093/brain/awab346)
[Suarez-Calvet M, Araque Caballero MA, et al, TMEM106B in presymptomatic and symptomatic C9orf72 mutation carriers (2020)](https://doi.org/10.1002/ana.25870)
[Nelson PT, Dickson DW, Trojanowski JQ, et al, Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report (2019)](https://doi.org/10.1093/brain/awz099)
[Ludtmann MH, Arber C, Joshi A, et al, TMEM106B overexpression causes lysosomal enlargement and reduces autophagic flux (2019)](https://doi.org/10.1242/jcs.229265)Pathway Diagram
The following diagram shows the key molecular relationships involving TMEM106B Protein (Transmembrane Protein 106B) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)