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10.1242-dmm.049323 |
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|a 17548403 (ISSN)
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|a TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic C. elegans
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|b Company of Biologists Ltd
|c 2022
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|z View Fulltext in Publisher
|u https://doi.org/10.1242/dmm.049323
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|a While amyloid (A) β and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in over half of patients with AD. Individuals with concomitant Aβ, tau, and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau, and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal C. elegans. We demonstrate that TDP-43 specifically enhances tau but not Aβ neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation, and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is critical to understand and ultimately treat mixed pathology AD. © 2022 Company of Biologists Ltd. All rights reserved.
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|a Alzheimer's disease
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|a amyloid β (Aβ)
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|a C. elegans
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|a proteotoxicity
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|a tau
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|a TDP-43
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|a Bird, T.D.
|e author
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|a Currey, H.N.
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|a Dirk Keene, C.
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|a Hincks, J.C.
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|a Kraemer, B.C.
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|a Latimer, C.S.
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|a Liachko, N.F.
|e author
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|a Stair, J.G.
|e author
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|t DMM Disease Models and Mechanisms
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