Abstract
The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.
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Acknowledgements
We thank our patients and their families for contributing to this research. This study was supported by the NIH (RO1 NS082265, P30 AG010124, U19 AG062418). Fei Mao is additionally supported by the National Natural Science Foundation of China (81700053) and Alice Chen-Plotkin by the Chan Zuckerberg Initiative Neurodegeneration Challenge, the American Heart Association/Allen Institute Brain Health Initiative, and the Parker Family Chair.
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Mao, F., Robinson, J.L., Unger, T. et al. TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy. Acta Neuropathol 142, 629–642 (2021). https://doi.org/10.1007/s00401-021-02330-2
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DOI: https://doi.org/10.1007/s00401-021-02330-2