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Funded Studies

Reversing Pre-existing Pathologies of Dopamine Neurons in an Alpha-synuclein Model

Objective/Rationale:             
Alpha-synuclein has been identified to play the central role in Parkinson’s disease. Genome-wide association studies confirm alpha-synuclein as a risk factor for sporadic Parkinson’s disease. Missense mutations and duplication/triplication of alpha-synuclein have been causally linked to familial Parkinson’s disease. Moreover, alpha-synuclein accumulation in neurons, especially in Lewy bodies in these neurons, is a major presentation in Parkinson’s disease (PD). Therefore, alpha-synuclein is a promising drug target in PD.

Project Description:             
To test potential therapies for slowing down dopamine neuron degeneration in Parkinson’s disease, we have generated a transgenic pre-clinical model for synucleinopathy in dopamine neurons. Our preliminary data show dopamine neurons have human alpha-synuclein expression and early-onset axonal and dendritic pathologies. We will further study whether this model recapitulates other cardinal features of dopamine pathologies in Parkinson’s disease, such as dopamine neuron death, Lewy body-like inclusion formation, levodopa-responsive movement impairments. We will focus on characterizing morphological abnormalities of dopamine neurons by electron microscopy, quantitative stereology and immunohistology. These characterizations of the model will provide trackable makers for testing potential therapies in reversing synucleinopathy in future drug discovery.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
This project is closely related to screening potential therapies in inhibiting alpha-synuclein-induced dopamine neuron pathologies and holds promises to accelerate future treatments for Parkinson’s disease. Moreover, this project will validate a useful in vivo preclinical model to study the mechanisms of alpha-synuclein toxicity in dopamine neurons.  

Anticipated Outcome:          
We anticipate that several reliable markers for dopamine neuron neuropathologies will be identified in this model. We expect that these markers can be quantitatively measured and, thus, facilitate assessing the efficacy of potential therapies targeting alpha-synuclein and its downstream molecular pathways. 

Final Outcome

Alpha-synuclein is the central player for Parkinson’s disease. Its point mutations and overexpression cause genetic forms of PD. In addition, it is also consistently linked to sporadic PD. Therefore, therapies to decrease alpha-synuclein level are promising in curing PD. However, it is unknown if deceasing alpha-synuclein can actually reverse pre-existing PD pathologies, as in the case for most of diagnosed PD patients. We were able to model the pre-existing PD pathologies in a transgenic mouse model and also study whether decreasing alpha-synuclein expression actually reverses PD pathologies. Encouragingly, we found decreasing alpha-synuclein level effectively reversed most of pre-existing PD pathologies. This finding strongly supports that decreasing alpha-synuclein level can be an effective therapy to treat PD. 


Researchers

  • Linan Chen, MD, PhD

    Chicago, IL United States


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