Objective/Rationale:
Mitochondrial dysfunction has been proposed as a key feature of progressive neuronal cell death in Parkinson’s disease. In particular, mitochondrial fission and fusion appear to be highly regulated mechanisms with considerable impact on mitochondrial integrity, formation of reactive oxygen species and release of pro-apoptotic proteins. Therefore, interfering with mitochondrial fission and downstream mechanisms of neuronal cell death may emerge as novel therapeutic strategies to prevent progressive neuronal loss in PD.
Project Description:
The first phase of the project addresses alterations of mitochondrial morphology in model systems of Parkinson’s disease including oxidative stress (SIN-1) and MPP+ toxicity in primary cultures of midbrain dopaminergic neurons and in neuronal cell lines. In addition, analyses of mitochondrial morphology, regulation of pro-apoptotic bcl-2 proteins, regulators of mitochondrial fusion and fission, and AIF translocation are performed in the pre-clinical model of MPTP toxicity. Novel small molecule inhibitors of Bid and Drp-1, and siRNA targeting regulators of mitochondrial integrity are applied in vitro and in vivo in order to validate potential therapeutic targets in these experimental models of PD.
Relevance to Treatment of Parkinson’s Disease:
Understanding the regulation of mitochondrial morphology and mitochondrial dysfunction and downstream mechanisms such as the nuclear translocation of AIF in models of ROS- or MPTP-induced neuronal death will lead to novel therapeutic strategies to prevent progressive neuronal death in PD. RNAi technology is applied to validate such potential therapeutic targets in vitro and in vivo as a basis for the focused development of neuroprotective drugs. In addition, the already available small molecule inhibitors of Bid and Drp-1 are neuroprotective drugs that are tested with the perspective for translational approaches in the near future.
Anticipated Outcome:
The proposed study provides novel insights into mechanisms of mitochondrial demise in model systems of oxidative stress-induced neuronal cell death relevant to PD and other neurodegenerative diseases. In particular, regulators of mitochondrial morphology, mitochondrial membrane integrity and downstream executors of apoptosis are validated as potential therapeutic targets for neuroprotective strategies in the treatment of PD.
Final Outcome
Dr. Culmsee was able to identify established and novel regulators of mitochondrial fission through the use of primary cultures of dopaminergic neurons. In addition, small molecule inhibitors and siRNA approaches were used to validate these findings in vitro and in vivo.