Funded Studies
This grant builds upon the research from a prior grant: Reversing Pre-existing Pathologies of Dopamine Neurons in an Alpha-synuclein Model
Promising Outcomes of Original Grant:
Alpha-synuclein is the central player for Parkinson’s disease. Therapies to decrease levels of alpha-synuclein are promising in curing PD. However, it is unknown if such therapies can actually reverse pre-existing PD pathologies, as is the case for most of diagnosed PD patients. We created strong PD pathologies in dopamine neurons of a transgenic pre-clinical model and found decreasing alpha-synuclein levels effectively reversed most of these pre-existing PD pathologies. This finding strongly supports that decreasing alpa-synuclein levels can be an effective therapy to treat PD.
Objectives for Supplemental Investigation:
Alpha-synuclein adopts several different forms/species, some of which are hypothesized to be instrumental in PD pathologies. Selectively targeting these toxic alpha-synuclein species might be more effective and, at same time, avoid interfering with normal functions of alpha-synuclein. Having found encouraging evidence that targeting alpha-synuclein might be the basis for promising therapies for Parkinson’s disease in our original funded research, we will continue to identify the toxic species of alpha-synuclein responsible for PD pathologies in dopamine neurons.
Importance of This Research for the Development of a New PD Therapy
We aim to identify the toxic alpha-synuclein species causing PD pathologies in this research. With current enormous efforts in developing inhibitors and tracers for alpha-synuclein aggregation for both therapeutic and diagnostic purposes for PD, identification and verification of toxic alpha-synuclein species in our model will provide an in vivo platform for testing these compounds. This research will be valuable to accelerate the drug discovery for PD.
Final Outcome
To find a cure for Parkinson's disease (PD), we need to identify and confirm drug candidates and underlying causes of disease they target. Pre-clinical models are indispensable to researchers working toward these goals. We have engineered several pre-clinical models of PD using a novel experimental method of DNA manipulation. Using these new models, we successfully validated underlying causes of PD, such as mutations (changes) in the alpha-synuclein and LRRK2 genes as well as damage to mitochondria (cell's powerhouses) and failure to break down damaged mitochondria. We also validated treatment strategies in development, such as those aiming to suppress alpha-synuclein production and rescue damaged mitochondria. We believe that our research tools and findings resulting from these studies will greatly accelerate the search for a cure.
November 2014
Presentations & Publications
Chen L, Xie Z, Turkson S, Zhuang X. A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci. 2015;35(3):890-905