TY - JOUR T1 - TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy JF - bioRxiv DO - 10.1101/2021.05.07.442949 SP - 2021.05.07.442949 AU - Fei Mao AU - John Robinson AU - Travis Unger AU - Marijan Posavi AU - Defne Amado AU - Lauren Elman AU - Murray Grossman AU - David Wolk AU - Edward Lee AU - Vivianna M. Van Deerlin AU - Sílvia Porta AU - Virginia Lee AU - John Trojanowski AU - Alice S. Chen-Plotkin Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/08/2021.05.07.442949.abstract N2 - 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. In order 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.Competing Interest StatementThe authors have declared no competing interest. ER -