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.

神经退行性疾病肌萎缩侧索硬化 (ALS) 和额颞叶变性伴 TAR DNA 结合蛋白 43 (TDP-43) 包涵体 (FTLD-TDP) 具有 TDP-43 聚集体的神经病理学特征。然而，控制 TDP-43 病理学严重程度和区域分布的因素（可能解释 ALS 和 FTLD-TDP 的不同临床表现）尚不清楚。在这里，我们研究了TMEM106B基因型的影响，这是一个与 FTLD-TDP 风险相关的基因座，以及C9orf72中的六核苷酸重复扩增， ALS 和 FTLD-TDP 的已知遗传原因，关于全球 TDP-43 病理学和 TDP-43 病理学在 899 例来自一系列神经退行性疾病的死后病例中的区域分布。我们发现，在 110 例 ALS 病例中，TMEM106B基因座前哨 SNP rs1990622 的次要 (C)-等位基因纯合子在全球以及特定脑区具有更多的 TDP-43 病理学。C9orf72扩增与 ALS 中更大的 TDP-43 病理学相似。然而，调整C9orf72扩增状态并不影响TMEM106B基因型和 TDP-43 病理学之间的关系。为了阐明这种关联的因果关系，我们直接操纵了 TMEM106B表达错误定位的 TDP-43 蛋白的诱导型细胞系统中的水平。我们发现 TMEM106B 的部分敲低，达到与 rs1990622 C 等位基因携带者的预期水平相似的水平，导致在该系统中形成更多的 TDP-43 细胞质聚集体，这些聚集体更难溶解。总之，我们的结果支持 TMEM106B 在改变 TDP-43 蛋白病发展中的因果作用。