GDNF alleviates depression in Parkinson's disease by inhibiting α-synuclein aggregation and facilitating DA transmission from VTA to NAc

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

Abstract Background Dopamine (DA) transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is strongly implicated in the development of depression in Parkinson's disease (PD). We have observed a decrease in DA levels caused by alpha-synuclein (α-syn) aggregation, which has received limited attention regarding its association with depression in PD. This study investigated the role of VTA-related α-syn aggregation in depression of PD, and explored whether gial cell line-derived neurotrophic factor (GDNF) can inhibit α-syn aggregation thereby improving depressive symptoms. Methods Here, α-syn aggregation and GDNF overexpression were induced in the VTA of C57BL/6J mice using adeno-associated viruses (AAV-SNCA, AAV-GDNF). Depression-like behavior was then evaluated, and the distribution of VTA- and NAc-related proteins, along with DA levels, were quantified. Subsequently, AAV-SNCA, AAV-GDNF, and cis-tracer virus were delivered into the VTA of DAT-cre mice via a cannula. The fluorescence intensity of the tracer in the VTA and NAc, as well as its colocalization with glutamate decarboxylase 67 isoforms (GAD67), were observed. Finally, in D2-cre mice, AAV-SNCA was injected into the VTA, and chemogenetic virus was infused into the ipsilateral NAc; depression-like behavior was then assessed before and after intraperitoneal administration of Clozapine N-oxide (CNO) in these mice. Results The mice with increased phosphorylated-α-syn (p-α-syn) in the VTA exhibited depressiion-like behavior, along with decreased tyrosine hydroxylase (TH) in the VTA, reduced expression of synapse-associated proteins and dopamine D2-type receptor (D2R) in the NAc, and diminished levels of DA in both the VTA and NAc. However, GDNF overexpression in the VTA, led to a decrease in p-α-syn expression and reversed the aforementioned phenomena. Furthermore, results from cis-tracer virus and Immunofluorescence (IF) assay revealed a reduction in transmission of DA from the VTA to the NAc in mice with α-syn aggregation, which can be reversed by GDNF overexpression. Additionally, chemogenetic virus-induced activation of D2R in the NAc significantly ameliorated depression-like behavior due to α-syn aggregation in the VTA. Conclusions The aggregation of α-syn within the VTA may play a crucial role in the pathogenesis of depression in PD, while GDNF can alleviate depression by inhibiting α-syn aggregation.

Related topics