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 divers...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002049 |
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| Summary: | 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-43C173/175S and TDP-43G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43C173/175S induced insoluble inclusions more robustly than TDP-43G298S did. In contrast, TDP-43G298S induced cell death more severely than TDP-43C173/175S. TDP-43G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43C173/175S. Instead, TDP-43C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43C173/175S 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. |
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| ISSN: | 1095-953X |