Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons. Aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the central nerve system (CNS) is a pathological hallmark of sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we report that the administration of spinal cord extracts from an ALS patient induces the formation of TDP-43 pathology that progressively spreads in a time-dependent manner in human induced pluripotent stem cells (iPSCs)-derived cerebral organoids. Pathogenic TDP-43 causes astrogliosis and cellular apoptosis, correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue.

Journal Link: 10.1101/2022.05.05.490760 Journal Link: Publisher Website Journal Link: Download PDF Journal Link: Google Scholar