Loss of TDP-43 function underlies hippocampal and cortical synaptic deficits in TDP-43 proteinopathies.
Mol Psychiatry
; 28(2): 931-945, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-34697451
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Neurodegenerativas
/
Proteinopatias TDP-43
/
Esclerose Lateral Amiotrófica
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article