Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging

Perneel, Jolien; Neumann, Manuela; Heeman, Bavo; Cheung, Siu Yin; Broeck, Marleen Van den; Wynants, Sarah; Baker, Matt; Vicente, Cristina T; Faura, Júlia; Rademakers, Rosa

doi:10.1007/s00401-022-02531-3

Cited by 31 publications

(42 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings are consistent with the identification of full-length TMEM106B as an endolysosomal transmembrane protein with the core domain localized to the vesicle lumen (12)(13)(14). However, consistent with a recent report that observed no relationship between TMEM106B immunoreactivity by IHC and TMEM106B haplotype (21), immunolabeling with our TMEM106B core antibody was unable to differentiate between risk haplotype or disease status by IHC (fig. S6).…”

Section: Characteristic Ftld-tdp (Nsupporting

confidence: 92%

“…Histological evaluation of postmortem FTLD-TDP brain tissue from carriers of the homozygous protective versus risk genotypes could provide clarity as to whether altered subcellular localization in the endolysosomal pathway might account for reduced accumulation of the TMEM106B S185 core, although this analysis is complicated by the current inability of antibodies to differentiate between full-length and insoluble TMEM106B core filaments by IHC. A recently generated antibody targeting the TMEM106B core domain (amino acids 239 to 250) was reported to exhibit specificity for C-terminal fragments of TMEM106B under denaturing conditions ( 21 , 47 ). However, given the observed discrepancy between TMEM106B core deposition measured by biochemical methods and TMEM106B abundance observed using histological methods ( 47 )—a finding replicated herein—we anticipate that additional antibody validation will reveal that TMEM106B core antibodies also detect and immunolabel both full-length and soluble, nonaggregated core by IHC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Marks,

Ayuso,

Carlomagno

et al. 2024

Sci. Transl. Med.

View full text Add to dashboard Cite

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

show abstract

Section: Characteristic Ftld-tdp (Nsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Marks,

Ayuso,

Carlomagno

et al. 2024

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…With respect to the phenotypic difference between FTD and ALS, a genetic analysis revealed homozygosity of minor protective allele of TMEM106B protects C9‐HRE carriers from developing FTD, but not from developing ALS (van Blitterswijk et al, 2014). Recently, it was reported that the C‐terminal fragment (CTF) of TMEM106B accumulates in the brain in an age‐dependent manner (Chang et al, 2022; Jiang et al, 2022; Perneel et al, 2023; Schweighauser et al, 2022). As a matter of course, the pathogenic contribution of TMEM106B‐CTF in the brain of C9‐FTD has begun to be analyzed, but no clear conclusion has yet been reached (Perneel et al, 2023).…”

Section: Rna Toxicity Versus Dpr Toxicitymentioning

confidence: 99%

“…Recently, it was reported that the C‐terminal fragment (CTF) of TMEM106B accumulates in the brain in an age‐dependent manner (Chang et al, 2022; Jiang et al, 2022; Perneel et al, 2023; Schweighauser et al, 2022). As a matter of course, the pathogenic contribution of TMEM106B‐CTF in the brain of C9‐FTD has begun to be analyzed, but no clear conclusion has yet been reached (Perneel et al, 2023).…”

Section: Rna Toxicity Versus Dpr Toxicitymentioning

confidence: 99%

Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

Mori

Gotoh

Ikeda

2023

Journal of Neurochemistry

View full text Add to dashboard Cite

An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of frontotemporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.

show abstract

“…The transmembrane protein 106B (TMEM106B) is known to be associated with risk in neurodegenerative diseases and specifically frontotemporal dementias; however, the relationship between TMEM106B and tau is not well understood [7,8]. At the cellular level, there is evidence that this protein is present in neurons, oligodendrocytes, astrocytes and microglia [8,9]. By cryo-EM, TMEM106B filaments were recently identified in postmortem brain tissue of individuals affected by neurodegenerative diseases and of individuals with no evidence of neurodegeneration [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Hoq

Bharath

Hallinan

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: The Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. Methods: We isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. Results: We determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. Conclusions: Our findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.

show abstract

Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging

Cited by 31 publications

References 41 publications

TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Contact Info

Product

Resources

About