Regulation of Cdc42 signaling by the dopamine D2 receptor in a mouse model of Parkinson’s disease

Abstract

Substantial spine loss in striatal medium spiny neurons (MSNs) and abnormal behaviors are common features of Parkinson's disease (PD). The caudate putamen (CPu) mainly contains MSNs expressing dopamine D1 receptor (dMSNs) and dopamine D2 receptor (iMSNs) exerting critical effects on motor and cognition behavior. However, the molecular mechanisms contributing to spine loss and abnormal behaviors in dMSNs and iMSNs under parkinsonian state remain unknown. In the present study, we revealed that Cell division control protein 42 (Cdc42) signaling was significantly decreased in the caudate putamen (CPu) in parkinsonian mice. In addition, overexpression of constitutively active Cdc42 in the CPu reversed spine abnormalities and improved the behavior deficits in parkinsonian mice. Utilizing conditional dopamine D1 receptor (D1R) or D2 receptor (D2R) knockout mice, we found that such a decrease under parkinsonian state was further reduced by conditional knockout of the D2R but not D1R. Moreover, the thin spine loss in iMSNs and deficits in motor coordination and cognition induced by conditional knockout of D2R were reversed by overexpression of constitutively active Cdc42 in the CPu. Additionally, conditional knockout of Cdc42 from D2R‐positive neurons in the CPu was sufficient to induce spine and behavior deficits similar to those observed in parkinsonian mice. Overall, our results indicate that impaired Cdc42 signaling regulated by D2R plays an important role in spine loss and behavioral deficits in PD.

Glutamate receptor-interacting protein 1 in D1- and D2-dopamine receptor-expressing medium spiny neurons differentially regulates cocaine acquisition, reinstatement, and associated spine plasticity

“…per mL. These promoters can initiate the expression of target proteins specifically in D1-MSNs or D2-MSNs of the NAc, as reported by previous research ( Ying et al, 2022 ).…”

Joint-tissue integrative analysis identifies high-risk genes for Parkinson’s disease

“…Interestingly, among the 159 identified risk genes for PD, several are enriched in these PD-related pathways. For example, genes such as SCNA, CDC42 ( Ying et al, 2022 ), EFNA1, MAPT ( Aarsland et al, 2017 ), and LZTS3 ( Li et al, 2023 ). Specifically, overexpressed SCNA, which codes for the protein alpha-synuclein, displayed aberrant synaptic nucleoprotein aggregation, causing neurotoxicity and neuronal death in PD ( Rocha et al, 2018 ).…”

“…This reduction ultimately leads to a decrease in the unnecessary elimination of dopamine neurons. Therefore, CDC42 inhibitors hold promise as a potential alternative for the treatment of PD ( Surviladze et al, 2010 ; Barcia et al, 2012 ; Ying et al, 2022 ). These findings provide valuable clues for in-depth research into their association and role in PD, indicating the need for further comprehensive investigation into PD risk factors.…”

Intelligence, education level, and risk of Parkinson’s disease in European populations: A Mendelian randomization study

“…Third, there is a number of potential genetic or biological association between IQ and PD. For example, CDC42, the corresponding gene of rs10917152, is associated with PD ( Ying et al, 2022 ). It has been shown that impaired CDC42 signaling regulated by dopamine D2 receptors leads to spine loss and behavioral deficits in PD ( Ying et al, 2022 ).…”

“…For example, CDC42, the corresponding gene of rs10917152, is associated with PD ( Ying et al, 2022 ). It has been shown that impaired CDC42 signaling regulated by dopamine D2 receptors leads to spine loss and behavioral deficits in PD ( Ying et al, 2022 ). ESSRG (a transcription factor estrogen-related receptor gamma), the corresponding gene of rs10779271, deficiency leads to the reduction of genes related to synaptic, mitochondrial function, and autophagy, which causes PD ( Fox et al, 2022 ).…”