Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.

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.

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

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population.