TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy

AbstractThe 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 atTMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions inC9orf72, 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 theTMEM106B 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 forC9orf72 expansion status did not affect the relationship betweenTMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulatedTMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown ofTMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmi...

Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research