Variation in TMEM106B in chronic traumatic encephalopathy - PubMed (original) (raw)

doi: 10.1186/s40478-018-0619-9.

Jonathan D Cherry 1 2 3, John F Crary 4, Yorghos Tripodis 5, Victor E Alvarez 1 2 3 6, Ian Mahar 1 2, Bertrand R Huber 1 2 3, Michael L Alosco 1 2, Raymond Nicks 6, Bobak Abdolmohammadi 1 2, Patrick T Kiernan 1 2 7, Laney Evers 1 2, Sarah Svirsky 1 3 6, Katharine Babcock 1 3 6, Hannah M Gardner 3, Gaoyuan Meng 3 6, Christopher J Nowinski 1 2 8, Brett M Martin 5, Brigid Dwyer 2 9, Neil W Kowall 1 2 3, Robert C Cantu 10 8 11 12, Lee E Goldstein 1 13 14 15, Douglas I Katz 2 9, Robert A Stern 1 2 10 12, Lindsay A Farrer 2 5 16 17 18, Ann C McKee 19 20 21 22 23, Thor D Stein 24 25 26 27

Affiliations

Variation in TMEM106B in chronic traumatic encephalopathy

Jonathan D Cherry et al. Acta Neuropathol Commun. 2018.

Abstract

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

Keywords: Chronic traumatic encephalopathy; Dementia; Football; Genetics; Neuroinflammation; TDP-43; TMEM106B; Tau; Traumatic brain injury.

PubMed Disclaimer

Conflict of interest statement

IRB approval for the brain donation program was obtained through the Boston University Alzheimer’s Disease & CTE Center and the Edith Nourse Rogers Memorial Veterans Hospital.

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Fig. 1

Inclusion flow chart for CTE Cases. Red curved arrows indicate participants that were excluded. Tissue was not available for genotyping for the following reasons: 1) consults with tissue returned to consulting neuropathologist; 2) only small fragments received; 3) tissue was significantly degraded and did not pass quality control for genotyping

Fig. 2

Fig. 2

Representative images of ptau (AT8) and neuroinflammation (CD68) staining by TMEM106B genotype. Positive staining for the respective proteins is in red while hematoxylin counterstain is blue. All images are from the DLFC at the depth of the cortical sulcus. Scale bars represent 500 μm (a–c) and 200 μm (d–f)

Similar articles

Cited by

References

    1. Alosco Michael L., Mez Jesse, Tripodis Yorghos, Kiernan Patrick T., Abdolmohammadi Bobak, Murphy Lauren, Kowall Neil W., Stein Thor D., Huber Bertrand Russell, Goldstein Lee E., Cantu Robert C., Katz Douglas I., Chaisson Christine E., Martin Brett, Solomon Todd M., McClean Michael D., Daneshvar Daniel H., Nowinski Christopher J., Stern Robert A., McKee Ann C. Age of first exposure to tackle football and chronic traumatic encephalopathy. Annals of Neurology. 2018;83(5):886–901. doi: 10.1002/ana.25245. - DOI - PMC - PubMed
    1. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–1593. doi: 10.1038/nn.4132. - DOI - PMC - PubMed
    1. Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, DeSaro P, Boylan KB, Graff-Radford NR, Wszolek ZK, Rademakers R, Boeve BF, McKee AC, Dickson DW. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol. 2015;130:877–889. doi: 10.1007/s00401-015-1502-4. - DOI - PMC - PubMed
    1. Bigio EH. Update on recent molecular and genetic advances in frontotemporal lobar degeneration. J Neuropathol Exp Neurol. 2008;67:635–648. doi: 10.1097/NEN.0b013e31817d751c. - DOI - PMC - PubMed
    1. Brady OA, Zheng Y, Murphy K, Huang M, Hu F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet. 2013;22:685–695. doi: 10.1093/hmg/dds475. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources