Parkinson’s disease (PD), is one of the leading causes of disabilities and death and afflicting millions of people worldwide. Effective treatments are desperately needed but the underlying molecular and cellular mechanisms of Parkinson’s destructive path are poorly understood. Mitochondria are cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration). Healthy cells have an elegant mitochondrial quality control system to clear dysfunctional mitochondria and prevent their resultant devastation. Based on my work that Parkinson’s associated proteins PINK1 and Parkin control mitochondrial transport that might be essential for damaged mitochondrial clearance, I hypothesize that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration. I will test this hypothesis in iPSC (inducible pluripotent stem cells) from Parkinson’s patients. This work will be a major step forward in understanding the cellular dysfunctions underlying Parkinson’s etiology, and promise hopes to battle against this overwhelming health danger to our aging population.
Parkinson's disease (PD), one of the most common neurodegenerative diseases, afflicts millions of people worldwide with tremendous global economic and societal burdens. About 500,000 people are currently living with PD in the U.S, and approximate 1/10 of them live in California. The number continues to soar as our population continues to age. An effective treatment is desperately needed but the underlying molecular and cellular mechanisms of PD’s destructive path remain poorly understood. This proposal aims to explore an innovative and critical cellular mechanism that controls mitochondrial transport and clearance via mitophagy in PD pathogenesis with elegant employment of bold and creative approaches to live image mitochondria in iPSC (inducible pluripotent stem cells)-derived dopaminergic neurons from Parkinson’s patients. This study is closely relevant to public health of the state of California and will greatly benefit its citizens, as it will illuminate the pathological causes of PD and provide novel targets for therapuetic intervention.
The mechanisms that underlie Parkinson’s Disease (PD), a debilitating neurodegenerative disorder afflicting millions of people worldwide, remain elusive. Dysfunction of mitochondria, our cells’ power plants, is considered a principal culprit in the death of dopaminergic neurons, the cell type affected in the brains of PD patients. In this Fundamental Mechanisms Award proposal, the applicant proposes to test the hypothesis that mitochondrial elimination (mitophagy) is impaired in PD, leading to an accumulation of damaged mitochondria which in turn causes neurodegeneration. The applicant proposes to differentiate dopaminergic neurons from induced pluripotent stem cells (iPSCs) from patients with familial PD, and to utilize them to identify cellular abnormalities through live imaging of mitochondrial transport and mitophagy and to investigate the role of a specific protein in impaired mitophagy and neurodegeneration.
Significance and Innovation
- Disease modifying treatments for PD are urgently needed. If successful, the study will have important implications for the understanding of neurodegeneration and for the development of new drugs for the treatment of PD.
- Some reviewers argued that this project focuses on a novel mechanism underlying PD, and were enthusiastic about the specific hypothesis under investigation. Others pointed out that related findings have already been reported, and thought it therefore unlikely that the proposed research would add significantly to current knowledge. They did, however, acknowledge that previous studies were performed using animal models, and that the proposed study would be the first to address these molecular mechanisms in neurons derived from PD patients.
- While the PI suggests that the protein under investigation may have relevance for clinical applications, reviewers pointed out that its role in an essential cellular process, mitochondrial trafficking, likely precludes it from being a direct target for future PD therapy development.
Feasibility and Experimental Design
- The project is overall well designed and based on extensive preliminary data. This strongly supports the idea that the proposed project will generate useful data.
- The experiments are well justified and include sophisticated live imaging. While the experiments are technically demanding, the key reagents are in place and the techniques are established.
- Reviewers noted that one of the proposed markers is not unique to mitophagy, necessitating the use of additional markers.
- The studies designed to rescue mitochondrial deficits by down-regulating the protein of interest lack detail. For instance, biochemical approaches are not described, and the hurdles imposed by the heterogeneity of differentiated cell populations did not receive appropriate attention.
Principal Investigator (PI) and Research Team
- While a new investigator, the PI is exceptionally well qualified to carry out this work. It is a logical extension of previous research that produced several publications in high impact journals.
- Reviewers expressed some concern that no evidence was provided of the applicant’s ability to differentiate dopaminergic neurons. An important contributor with relevant expertise is mentioned and some reviewers felt that this expert’s inclusion as a collaborator would have strengthened the application. Others were however confident that the proximity of the two laboratories will enable necessary support.
- The PI is embedded in a rich scientific environment.
Responsiveness to the RFA
- The project is fully aligned with the requirements of the RFA, investigating the molecular mechanisms underlying PD in iPSC-derived neurons.