TMEM106B

TMEM106B
Identifiers
Aliases	TMEM106B , transmembrane protein 106B, HLD16
External IDs	OMIM: 613413 MGI: 1919150 HomoloGene: 56806 GeneCards: TMEM106B
Gene location (Human)
Chr.	Chromosome 7 (human)
End	12,243,367 bp
Gene location (Mouse)
Chr.	Chromosome 6 (mouse)
End	13,089,268 bp
RNA expression pattern
	Top expressed in
	corpus epididymis; ; caput epididymis; ; retinal pigment epithelium; ; superior vestibular nucleus; ; internal globus pallidus; ; subthalamic nucleus; ; cerebellar vermis; ; seminal vesicula; ; palpebral conjunctiva; ; postcentral gyrus;
	Top expressed in
	interventricular septum; ; Region I of hippocampus proper; ; epithelium of stomach; ; sciatic nerve; ; iris; ; superior colliculus; ; myocardium of ventricle; ; extraocular muscle; ; olfactory tubercle; ; retinal pigment epithelium;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	protein binding ; molecular function ;
Cellular component	integral component of membrane ; lysosomal membrane ; late endosome membrane ; membrane ; lysosome ; endosome ;
Biological process	lysosome localization ; dendrite morphogenesis ; lysosome organization ; lysosomal transport ; positive regulation of dendrite development ;
	Sources:Amigo / QuickGO
Orthologs
	54664
	71900
	ENSG00000106460
	ENSMUSG00000029571
	Q9NUM4
	Q80X71
	NM_001134232 ; NM_018374
	NM_027992
	NP_001127704 ; NP_060844 ; NP_001127704.1 ; NP_060844.2
	NP_082268
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated January 23, 2024

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene.^[5] It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.^[6]^[7]^[8]

Structure
Gene
Protein
Function
Lysosomal size
Lysosomal trafficking
Lysosomal pH
Clinical implications
Frontotemporal dementia
Amyotrophic lateral sclerosis
Alzheimer's disease
Chronic traumatic encephalopathy
Parkinson disease
Interactions
Progranulin and granulin
Vacuolar ATPase
Microtubule associate protein 6
References
Further reading

Structure

Gene

In humans,TMEM106B is found on chromosome 7 at positions 12211270 - 12243367, totaling 32097 base pairs. ^[9] The gene includes 9 exons and can give rise to 2 different isoforms, T185 and S185, which are formed by the risk and protective haplotypes, respectively.^[9]^[10]^[11]

Protein

TMEM106B is composed of 274 amino acids and it has a molecular weight of 31kDa.^[10] It is found in the membrane of a lysosome (transmembrane protein) and has its highest expression in the central nervous system, specifically within neurons and oligodendrocytes.^[12] The protein can be divided into 3 domains; N-terminal cytosolic domain, a transmembrane domain, and a C-terminal domain containing five N-glycosylation sites in the lumen.^[12]^[13] The exact mechanism of proteolytic processing for TMEM106B is not completely understood, but a protease cleaves the protein which releases the C-terminal domain into the lumen of the lysosome and creates a N-terminal fragment on the lysosomal membrane, which is further cleaved and processed by other proteases. The mechanisms behind the proteolysis of TMEM106B is of interest because it is thought to be a factor in what gives rise to TMEM106B fibril formation.^[11]

Fibrils

TMEM106B can form amyloid fibrils in a variety of neurodegenerative diseases and in neurologically healthy individuals, which have been structurally characterized by Cryo-EM. They can be made up of a single rod-like structure or a doublet of filaments forming a twisted ribbon, of which several polymorphisms have been identified; 4 singlets and 2 doublets. There has been no clear association between any of the polymorphisms to disease. The structure of the different polymorphisms is relatively conserved in the N-terminus, core, glycosylation sites (N145, N151, N164, and N183), and a disulfide bond between C214 an C253, the difference in structure is primarily within the C-terminal region.^[11]

Example of a TMEM106B singlet fibril structure. Obtained from Protein Data Bank^[14] and rendered on Chimera. ^[15]
Example of a TMEM106B doublet fibril structure. Obtained from Protein Data Bank^[16] and rendered on Chimera.^[17]

Function

TMEM106B is a transmembrane lysosomal protein that is involved in several key functions for the lysosome. The lysosome is the organelle that clears out debris and unnecessary proteins.

Lysosomal size

Studies in cell lines have shown that over-expression of TMEM106B leads to larger lysosomes, which causes a negative-stress response within the cell and cell death.^[19] It is thought that lysosomal size may be partially dependent on pH and successful trafficking, as problems in either of these functions leads to clustering lysosomes and formation of large swollen vacuoles. ^[20]

Lysosomal trafficking

Typically, lysosomes are trafficked along a microtubule by a motor protein and it has been observed that TMEM106B may play an important role in this process. ^[18] In knock-out studies of TMEM106B inappropriate clustering of lysosomes is observed at the nucleus, and it has been shown this phenotype can be rescued by re-introducing TMEM106B into the system.^[19]^[20] In addition, it has been observed that knock-out of TMEM106B in mice leads to increased retrograde transport of lysosomes causing large lysosomal vacuoles to form at the distal end of neurons.^[20] TMEM106B has been shown to interact with microtubule associated protein 6 (MAP6), and it is thought that this interaction inhibits the retrograde transport of lysosomes, assisting with appropriate trafficking of lysosomes or inability to be transported along the microtubule by motor proteins.^[21]

Lysosomal pH

Lysosome are typically at an acidic pH of 4.5-5, maintaining this is very important to a lysosomes ability to perform degradation.^[22] Vacuolar ATPase (vATPase) maintains the acidic pH in lysosomes and it has been shown that TMEM106B interacts with accessory proteins of vATPase. When TMEM106B levels are increased a reduction in vATPase activity is observed and the lysosome is unable to maintain an acidic environment.^[19]

Clinical implications

Frontotemporal dementia

Frontotemporal dementia (FTLD) is the third most common neurodegenerative disease after AD and Parkinson disease. Many patients with FTLD have aggregates containing TDP-43, an RNA binding protein.^[23] A study performed in 515 FTLD-GRN with TDP-43 inclusion cases, including 89 individuals carrying pathogenic mutations in the granulin (GRN) gene, a known cause of familial FTLD-GRN identified a single nucleotide polymorphism (SNP), rs1990622, located 6.9 kilobases downstream of the TMEM106B gene (chromosome 7p21) as a genome-wide signal.^[24] Further studies have identified other SNPs that are associated with an increased risk of FTLD-GRN, rs1990621, rs1990620, rs1020004, rs6966915 and rs3173615. In addition to increased disease risk, rs1990620 is associated with worse cognitive decline and a reduction in brain size (increase neurodegeneration) and rs19906221 has been associated with decreased neuronal proportion. ^[23]^[25]

There are other forms of FTLD which are defined by their pathology or primary genetic mutations. Another subset of FTLD that has been evaluated for its association to TMEM106B are those with a C90RF72 mutation (FTLD-C9ORF72). Two of the SNPs previously identified as risk factors for FTLD-GRN, rs1990622 and rs3173615, were found to be associated with FTLD-C90RF72. The major allele of these SNPs were identified as a risk factor, while the minor allele was found to be protective. ^[23]^[26]

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive loss of motor neurons that control movement. TDP-43 aggregates and C9ORF72 mutations have been identified as important pathological and genetic markers, and therefore TMEM106B was investigated for its potential association to ALS. ^[27] Surprisingly, there was no association in TMEM106B genotype to disease risk, but the minor allele of rs1990622 has been shown to be associated with preserved cognition. ^[23]

Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disordered characterized by cognitive decline and dementia. TMEM106B and APOE4 polymorphisms have been found to interact and increase risk of AD.^[23] Recent genome-wide association study (GWAS) has found that genetic variations in TMEM106 are associated with late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations change the degradation pathways of misfolded protein contributing misfolded β-amyloid accumulation and plaque formation.^[28]

Chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated to exposure with repetitive head impacts. TMEM106B was evaluated for its association to CTE as neuroinflammation and TDP-43 pathology are common features of this disease. A SNP, rs3173615, specifically the minor allele was found to be associated with a protective phenotype in CTE cases, showing reduced phosphorylated tau and decreased neuroinflammation, but no association to TDP-43 pathology. ^[23]

Parkinson disease

Parkinson's disease (PD) is the second most common neurodegenerative disease that primarily effects the motor system, but also has unique cognitive symptoms. As TMEM106B has been linked to several neurodegenerative disease, it was investigated for its association to PD and it was found to be associated with cognitive decline. ^[23]

Summary table of TMEM106B SNPs and their association to neurodegenerative disease. Table was adapted from Feng et al. (2021) ^[23]
Disease	SNP	Major Allele:Minor Allele	Phenotypes associated with SNP(s)
FTLD-GRN	rs1990622 rs1990621 rs1990620 rs1020004 rs6966915 rs3173615	T:C C:G A:G A:G C:T C:G	All major alleles associated with increased risk Most significantly associated SNP, rs1990622, major allele increases odds by ~62%^[23]
FTLD-C9ORF72	rs1990622 rs3173615	T:C C:G	Major allele associated with increased risk rs1990622 major allele increases odds by ~56%^[23] Minor allele associated with decreased risk rs1990622 minor allele decreases odds by ~64%^[23]
ALS	rs1990622	T:C	Minor allele associated with preserved cognition^[23]
AD	rs1990622 rs1990620 rs1595014	T:C A:G T:A	Major allele increases risk in APOE4 carriers
CTE	rs3173615	C:G	Minor allele associated with protective phenotype Minor allele reduces odds of developing dementia by ~60% ^[29]
PD	rs1990622	T:C	Major allele associated with more rapid cognitive decline

Interactions

Progranulin and granulin

Progranulin (PGRN) is a glycoprotein that has been identified as another important protein for lysosomal function in neurons and microglia, particularly during aging and neurodegenerative disease. ^[30] As TMEM106B has been associated with increased risk of FTLD-GRN, it was investigated for its association to PGRN and was found that the risk allele was associated to decreased levels of PGRN. ^[31] Studies performed in vitro and in vivo, increasing and decreasing levels of TMEM106B, found that PGRN seems to be indirectly modulated by TMEM106B by impacting lysosomal functions. ^[31]

Cruchaga et al.,,^[32] analyzed if TMEM106B variants modify GRN levels. The found that The risk allele of rs1990622 was associated with a mean decrease of the age at onset of 13 years (P = 9.9 × 10⁻⁷) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10⁻⁴) and GRN mutation carriers (P = 0.0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (p.T185S) in perfect linkage disequilibrium with rs1990622, that my represent the functional variant driving the association. In summary, these results indicate that the association of rs1990622 with age at onset explains, in part, the wide range in the onset of disease among GRN mutation carriers. The rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN. ^[33]

Vacuolar ATPase

vATPases are proton pumps found on cell membranes that are in charge of acidifying multiple organelles, including lysosomes. It has been shown that increase levels of TMEM106B leads to improper acidification of lysosomes through its interaction with vATPases. This interaction is thought to be caused by TMEM106B binding directly to AP1 subunit of vATPase. ^[34]

Microtubule associate protein 6

MAP6 is a microtubule protein that helps stabilize microtubules and provide guidance to signal proteins to microtubules. TMEM106B binds to the C-terminus of MAP6, which helps traffic lysosome to microtubules for transport. It has been shown with increased level of TMEM106B there is excessive binding to MAP6 which impairs transport of the lysosome along the microtubule and leads to accumulation of swollen vacuoles in inappropriate places within the cell. ^[34]

Related Research Articles

Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as behavioral or language disorders with gradual onsets. Common signs and symptoms include significant changes in social and personal behavior, apathy, blunting of emotions, and deficits in both expressive and receptive language. Currently, there is no cure for FTD, but there are treatments that help alleviate symptoms.

Degenerative disease is the result of a continuous process based on degenerative cell changes, affecting tissues or organs, which will increasingly deteriorate over time.

The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.

Hippocampal sclerosis (HS) or mesial temporal sclerosis (MTS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus. Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis. Hippocampal sclerosis occurs in 3 distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury.

<span class="mw-page-title-main">Tauopathy</span> Medical condition

Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates. The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimer's disease or play a peripheral role is unknown.

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.

26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 gene.

TAR DNA-binding protein 43 is a protein that in humans is encoded by the TARDBP gene.

Tubulin polymerization-promoting protein is a protein that in humans is encoded by the TPPP gene.

Formin-like protein 2 is a protein that in humans is encoded by the FMNL2 gene.

Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.

C9orf72 is a protein which in humans is encoded by the gene C9orf72.

Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur independently of the amyloid plaques of Alzheimer's disease (AD). The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary and Peter T. Nelson. Despite some controversy, the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.

Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene. PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. PLD3 serves as a ssDNA 5' exonuclease in antigen presenting cells. PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in the endoplasmic reticulum (ER) and the lysosome.

LATE is a term that describes a prevalent condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome. In other words, the symptoms of LATE are similar to those of Alzheimer's disease.

Carlos Cruchaga is a human genomicist with expertise in multi-omics, informatics, and neurodegeneration, with a focus on Alzheimer's and Parkinson's Disease. He is a Professor of Psychiatry, Neurology and Genetics and Washington University School of Medicine. He is founding director of the Neurogenomics and Informatic (NGI) center at Washington University School of Medicine.

Granulovacuolar degeneration refers to the occurrence within neurons of abnormal, fluid-filled bubbles (vacuoles) containing a dense proteinaceous granule. Granulovacuoles occur most commonly in pyramidal neurons of the hippocampus. They are present in small numbers in non-demented elderly people, but increase in frequency in Alzheimer's disease and other tauopathies. In Alzheimer's disease, granulovacuoles proliferate stage-wise in different brain areas, and their prevalence is correlated with the degree of tauopathy, Abeta plaque pathology, and cerebral amyloid angiopathy. Immunohistochemical analyses have found that the inner granule includes several proteins, including tubulin tau protein, TDP-43 and others. Although granulovacuoles and their functional significance are still poorly understood, they have been compared to autophagic vacuoles

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000106460 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029571 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Entrez Gene: TMEM106B transmembrane protein 106B".
↑ Feng T, Lacrampe A, Hu F (2021). "Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders". Acta Neuropathologica. 141 (3): 327–339. doi:10.1007/s00401-020-02246-3. ISSN 0001-6322. PMC 8049516 . PMID 33386471.
↑ Perneel J, Rademakers R (2022). "Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease". Acta Neuropathologica. 144 (5): 807–819. doi:10.1007/s00401-022-02486-5. ISSN 0001-6322. PMC 9547799 . PMID 36056242.
↑ Nicholson AM, Rademakers R (2016). "What we know about TMEM106B in neurodegeneration". Acta Neuropathologica. 132 (5): 639–651. doi:10.1007/s00401-016-1610-9. ISSN 0001-6322. PMC 5074873 . PMID 27543298.
1 2 "Entrez Gene: TMEM106B transmembrane protein 106B".
1 2 "TMEM106B Gene - GeneCards | T106B Protein | T106B Antibody". www.genecards.org. Retrieved 2022-09-29.
1 2 3 Perneel J, Rademakers R (2022). "Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease". Acta Neuropathologica. 144 (5): 807–819. doi:10.1007/s00401-022-02486-5. ISSN 0001-6322. PMC 9547799 . PMID 36056242.
1 2 Bank RP. "RCSB PDB - 7SAS: Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 3". www.rcsb.org. Retrieved 2022-11-14.
↑ Feng T, Lacrampe A, Hu F (2021). "Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders". Acta Neuropathologica. 141 (3): 327–339. doi:10.1007/s00401-020-02246-3. ISSN 0001-6322. PMC 8049516 . PMID 33386471.
↑ Bank RP. "RCSB PDB - 7QWM: TMEM106B filaments with Fold III from Multiple system atrophy (case 17)". www.rcsb.org. Retrieved 2022-11-16.
↑ "UCSF Chimera Home Page". www.cgl.ucsf.edu. Retrieved 2022-11-17.
↑ Bank RP. "RCSB PDB - 7QVF: TMEM106B filaments with Fold I-d from Multiple system atrophy (case 18)". www.rcsb.org. Retrieved 2022-11-16.
↑ "UCSF Chimera Home Page". www.cgl.ucsf.edu. Retrieved 2022-11-17.
1 2 Root J, Merino P, Nuckols A, Johnson M, Kukar T (2021). "Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis". Neurobiology of Disease. 154: 105360. doi:10.1016/j.nbd.2021.105360. ISSN 1095-953X. PMC 8113138 . PMID 33812000.
1 2 3 Feng T, Lacrampe A, Hu F (2021). "Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders". Acta Neuropathologica. 141 (3): 327–339. doi:10.1007/s00401-020-02246-3. ISSN 0001-6322. PMC 8049516 . PMID 33386471.
1 2 3 Nicholson AM, Rademakers R (2016). "What we know about TMEM106B in neurodegeneration". Acta Neuropathologica. 132 (5): 639–651. doi:10.1007/s00401-016-1610-9. ISSN 0001-6322. PMC 5074873 . PMID 27543298.
↑ Root J, Merino P, Nuckols A, Johnson M, Kukar T (2021). "Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis". Neurobiology of Disease. 154: 105360. doi:10.1016/j.nbd.2021.105360. ISSN 0969-9961. PMC 8113138 . PMID 33812000.
↑ Yang C, Wang X (2021-05-05). "Lysosome biogenesis: Regulation and functions". The Journal of Cell Biology. 220 (6): e202102001. doi:10.1083/jcb.202102001. ISSN 0021-9525. PMC 8105738 . PMID 33950241.
1 2 3 4 5 6 7 8 9 10 11 12 13 Feng T, Lacrampe A, Hu F (2021). "Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders". Acta Neuropathologica. 141 (3): 327–339. doi:10.1007/s00401-020-02246-3. ISSN 0001-6322. PMC 8049516 . PMID 33386471.
↑ Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, et al. (March 2010). "Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions". Nature Genetics. 42 (3): 234–239. doi:10.1038/ng.536. PMC 2828525 . PMID 20154673.
↑ van der Zee J, Van Broeckhoven C (2011). "TMEM106B a novel risk factor for frontotemporal lobar degeneration". Journal of Molecular Neuroscience. 45 (3): 516–521. doi:10.1007/s12031-011-9555-x. ISSN 1559-1166. PMC 3207134 . PMID 21614538.
↑ Cooper-Knock J, Shaw PJ, Kirby J (2014). "The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype". Acta Neuropathologica. 127 (3): 333–345. doi:10.1007/s00401-014-1251-9. ISSN 1432-0533. PMC 3925297 . PMID 24493408.
↑ St Martin JL, Wang L, Kaprielian Z (2020-01-18). "Toxicity in ALS: TDP-43 modifiers and C9orf72". Neuroscience Letters. 716: 134621. doi:10.1016/j.neulet.2019.134621. ISSN 1872-7972. PMID 31726180. S2CID 207974038.
↑ Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. (September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics. 53 (9): 1276–1282. doi:10.1038/s41588-021-00921-z. hdl: 1871.1/61f01aa9-6dc7-4213-be2a-d3fe622db488 . PMC 10243600 . PMID 34493870. S2CID 237442349.
↑ Abdolmohammadi B, Dupre A, Evers L, Mez J (2020). "Genetics of Chronic Traumatic Encephalopathy". Seminars in Neurology. 40 (4): 420–429. doi:10.1055/s-0040-1713631. ISSN 1098-9021. PMID 32712945. S2CID 220798883.
↑ Rhinn H, Tatton N, McCaughey S, Kurnellas M, Rosenthal A (2022). "Progranulin as a therapeutic target in neurodegenerative diseases". Trends in Pharmacological Sciences. 43 (8): 641–652. doi: 10.1016/j.tips.2021.11.015 . ISSN 1873-3735. PMID 35039149. S2CID 245995434.
1 2 Feng T, Lacrampe A, Hu F (2021). "Physiological and pathological functions of TMEM106B: A gene associated with brain aging and multiple brain disorders". Acta Neuropathologica. 141 (3): 327–339. doi:10.1007/s00401-020-02246-3. ISSN 0001-6322. PMC 8049516 . PMID 33386471.
↑ Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, et al. (May 2011). "Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels". Archives of Neurology. 68 (5): 581–586. doi: 10.1001/archneurol.2010.350 . PMC 3090529 . PMID 21220649.
↑ Paushter DH, Du H, Feng T, Hu F (2018). "The lysosomal function of progranulin, a guardian against neurodegeneration". Acta Neuropathologica. 136 (1): 1–17. doi:10.1007/s00401-018-1861-8. ISSN 1432-0533. PMC 6117207 . PMID 29744576.
1 2 Root J, Merino P, Nuckols A, Johnson M, Kukar T (2021). "Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis". Neurobiology of Disease. 154: 105360. doi:10.1016/j.nbd.2021.105360. ISSN 0969-9961. PMC 8113138 . PMID 33812000.