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Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.

ABSTRACT: TMEM106B, encoding a lysosome membrane protein, has been recently associated with brain aging, hypomyelinating leukodystrophy and multiple neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). During the past decade, considerable progress has been made towards our understanding of the cellular and physiological functions of TMEM106B. TMEM106B regulates many aspects of lysosomal function, including lysosomal pH, lysosome movement, and lysosome exocytosis. Both an increase and decrease in TMEM106B levels result in lysosomal abnormalities. In mouse models, TMEM106B deficiency leads to lysosome trafficking and myelination defects and FTLD related pathology. In humans, alterations in TMEM106B levels or function are intimately linked to neuronal proportions, brain aging, and brain disorders. Further elucidation of the physiological function of TMEM106B and changes in TMEM106B under pathological conditions will facilitate therapeutic development to treat brain disorders associated with TMEM106B.

SUBMITTER: Feng T

PROVIDER: S-EPMC8049516 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.

Feng Tuancheng T Lacrampe Alexander A Hu Fenghua F

Acta neuropathologica 20210101 3

TMEM106B, encoding a lysosome membrane protein, has been recently associated with brain aging, hypomyelinating leukodystrophy and multiple neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). During the past decade, considerable progress has been made towards our understanding of the cellular and physiological functions of TMEM106B. TMEM106B regulates many aspects of lysosomal function, including lysosomal p ...[more]

PMID: 33386471

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Project description:BackgroundStudying structural brain aging is important to understand age-related pathologies, as well as to identify the early manifestations of the Alzheimer's disease (AD) continuum. In this study, we investigated the long-term trajectory of physiological and pathological brain aging in a large number of participants ranging from the 50s to over 80 years of age.ObjectiveTo explore the distinct brain regions that distinguish pathological brain aging from physiological brain aging using sophisticated measurements of cortical thickness.MethodsA total of 2,823 cognitively normal (CN) individuals and 2,675 patients with AD continuum [874 with subjective memory impairment (SMI), 954 with amnestic mild cognitive impairment (aMCI), and 847 with AD dementia] who underwent a high-resolution 3.0-tesla MRI were included in this study. To investigate pathological brain aging, we further classified patients with aMCI and AD according to the severity of cognitive impairment. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age, diagnostic groups, and cortical thickness.ResultsAging extensively affected cortical thickness not only in CN individuals but also in AD continuum patients; however, the precuneus and inferior temporal regions were relatively preserved against age-related cortical thinning. Compared to CN individuals, AD continuum patients including those with SMI showed a decreased cortical thickness in the perisylvian region. However, widespread cortical thinning including the precuneus and inferior temporal regions were found from the late-stage aMCI to the moderate to severe AD. Unlike the other age groups, AD continuum patients aged over 80 years showed prominent cortical thinning in the medial temporal region with relative sparing of the precuneus.ConclusionOur findings suggested that the precuneus and inferior temporal regions are the key regions in distinguishing between physiological and pathological brain aging. Attempts to differentiate age-related pathology from physiological brain aging at a very early stage would be important in terms of establishing new strategies for preventing accelerated pathological brain aging.

Project description:Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

Project description:BackgroundSingle nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear.MethodsWe utilized RNA sequencing data derived from temporal cortex (TCX) and cerebellum (CER) from 312 North American Caucasian subjects neuropathologically diagnosed with Alzheimer's disease, progressive supranuclear palsy, pathological aging or normal controls to analyze transcriptome signatures associated with the risk (TT) and protective (SS) TMEM106B haplotypes. In cohorts matched for disease phenotype, we used Analysis of Variance (ANOVA) to identify differentially expressed genes and Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene networks associated with the risk and protective TMEM106B haplotypes.ResultsA total of 110 TCX and 116 CER samples were included in the analyses. When comparing TT to SS carriers, we detected 593 differentially expressed genes in TCX and 7 in CER. Gene co-expression network analyses further showed that in both TCX and CER the SS haplotype was positively correlated with gene networks involved in synaptic transmission, whereas the TT haplotype was positively correlated with gene networks enriched for immune response. Gene expression patterns of 5 cell-type-specific markers revealed significantly reduced expression of the neuronal marker and relative increases in all other cell markers in TT as compared to SS carriers in TCX with a similar but non-significant trend in CER.ConclusionsBy comparing the common TMEM106B risk and protective haplotypes we identified significant and partly conserved transcriptional differences across TCX and CER and striking changes in cell-type composition, especially in TCX. These findings illustrate the profound effect of TMEM106B haplotypes on brain health and highlight the importance to better understand TMEM106B's function and dysfunction in the context of neurodegenerative diseases.

Dataset Information

Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.

Publications

Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.

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