Calcineurin inhibition protects against dopamine toxicity and attenuates behavioral decline in a Parkinson’s disease model

Abstract

Background Parkinson’s disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation. Results Here, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered. Conclusions In this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.

Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease

“…It is an option for those patients no longer controlled well by dopaminerelated drugs. However, current PD treatment provides symptomatic relief for the motor problems but does not prevent or slow the process of PD (Mondal et al, 2023).…”