Objective: In this study, our first aim was to develop a model for Parkinson’s disease (PD) that would exhibit the alpha-synuclein (αSyn) aggregation pathology and lead to degeneration of the nigral dopamine (DA) neurons over an optimal time course. The second aim of the project was to test the effects of CDNF on protein aggregation, neuroprotection, and restoration in this novel model of PD.
Background: Drug research and development depend heavily on results obtained from pre-clinical studies. PD drug research lacks a pre-clinical model that would recapitulate both formation of Lewy body (LB)-like inclusions and occurrence of robust DA neuron death within an optimal timeframe. Consequently, the existing therapies for PD mainly aim at mitigating the symptoms of the disease and do not stop or even slow down the degeneration of nigrostriatal DA neurons. Cerebral dopamine neurotrophic factor (CDNF) has shown evidence for neuroprotection and restoration in PD animal models and it recently reached its primary safety and tolerability endpoint in phase I/II clinical trial for PD.
Method: To develop our PD model, we combined an additional stressor with the pre-formed αSyn fibrils in embryonic primary midbrain cultures and in vivo in mice. The progression of pathology was analyzed by quantifying the intraneuronal pS129 aSyn-positive inclusions as well as DA neuron count. In the in vivo study, the quantification was done at different time points, correlating them with the deficits in the motor behavior of mice monitored throughout the experiment.
Results: The combination model has been characterized by quantifying DA neuron count and paSyn-positive LB-like aggregation. The analysis of the effects of CDNF in this model is currently under progress and will be discussed in the congress.
Conclusion: We conclude that combining aSyn fibrils with one additional stressor is not enough to mirror the characteristics of a multifactorial and complex disease such as PD. This study provides sufficient data in support of the need for combining several different stressors for generating better PD models, instead of evaluating drug effects based on a single stressor-induced PD model.
To cite this abstract in AMA style:
A. Singh, A. Panhelainen, M. Voutilainen. Effect of CDNF in a novel combination stressor model of Parkinson’s disease [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/effect-of-cdnf-in-a-novel-combination-stressor-model-of-parkinsons-disease/. Accessed September 7, 2024.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-cdnf-in-a-novel-combination-stressor-model-of-parkinsons-disease/