Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain

In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.PMID:38194085 | DOI:10.1007/s00018-023-05066-2

Source: Cellular and Molecular Life Sciences : CMLS - January 9, 2024 Category: Cytology Authors: Longhong Zhu Fuyu Deng Dazhang Bai Junqi Hou Qingqing Jia Chen Zhang Kaili Ou Shihua Li Xiao-Jiang Li Peng Yin Source Type: research