TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model.

TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43 and TDP-43 as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43 induced insoluble inclusions more robustly than TDP-43 did. In contrast, TDP-43 induced cell death more severely than TDP-43. TDP-43 was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43. Instead, TDP-43 was frequently trapped in the axon initial segments. Finally, TDP-43 was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43 to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.