Abstract
TDP-43 proteinopathy is linked to neurodegenerative diseases that feature synaptic loss in the cortex and hippocampus, although it remains unclear how TDP-43 regulates mature synapses. We report that, in adult mouse hippocampus, TDP-43 knockdown, but not overexpression, induces robust structural and functional damage to excitatory synapses, supporting a role for TDP-43 in maintaining mature synapses. Dendritic spine loss induced by TDP-43 knockdown is rescued by wild-type TDP-43, but not ALS/FTLD-associated mutants, suggesting a common TDP-43 functional deficiency in neurodegenerative diseases. Interestingly, M337V and A90V mutants also display dominant negative activities against WT TDP-43, partially explaining why M337V transgenic mice develop hippocampal degeneration similar to that in excitatory neuronal TDP-43 knockout mice, and why A90V mutation is associated with Alzheimer’s disease. Further analyses reveal that a TDP-43 knockdown-induced reduction in GluN2A contributes to synaptic loss. Our results show that loss of TDP-43 function underlies hippocampal and cortical synaptic degeneration in TDP-43 proteinopathies.
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Acknowledgements
We, at the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, thank the following agencies for their generous funding: Project supported by National Natural Science Foundation of China to YC (91849204, 31671044); National Program on Key Research Project of China to YC (2016YFA0501901); Shanghai Municipal Science and Technology Major Project to YC (Grant No. 2019SHZDZX02); Natural Science Foundation of Shanghai to GY (19ZR1468600, 201409003800). National Program on Key Basic Research Project of China to YZ (2016YFA0501900 and 2016YFA0501904), the National Natural Science Foundation of China to YZ (32071245 and 31671428), Natural Science Foundation of Shanghai to YZ (20ZR1474400), and the Shanghai Municipal Science and Technology Major Project (Grant no. 2019SHZDZX02) to YZ.
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Concept, design and supervision of the study: YC, YG. JN, YR performed all experiments and data analysis unless otherwise stated. JN, TS performed recording of cortical pyramidal cells in acute brain slices with patch clamp. JN, CF performed behavioral analysis. JN, YR, JZ, YL performed plasmids construction. YR, DL, JZ, YL performed RNAseq data analysis. YC, YG, YZ, YF, NL supervised the project and interpreted data. All authors read and approved the final version of the manuscript.
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Ni, J., Ren, Y., Su, T. et al. Loss of TDP-43 function underlies hippocampal and cortical synaptic deficits in TDP-43 proteinopathies. Mol Psychiatry 28, 931–945 (2023). https://doi.org/10.1038/s41380-021-01346-0
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DOI: https://doi.org/10.1038/s41380-021-01346-0
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