Mitochondria are a 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. It is not surprising that the impairment in this mitochondrial quality control system has been linked to Parkinson’s disease (PD), one of the most common neurodegenerative diseases. Based on my work that Parkinson’s associated proteins PINK1 and Parkin halt mitochondrial transport that might be essential for the damaged mitochondrial clearance, I hypothesized that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration, in the original application. For the past year, we have made substantial progress in achieving the specific aims. Briefly, we found that the pathogenic G2019S mutation in LRRK2 increases mitochondrial movement and disrupts mitochondrial quality control. These functional deficits are present in multiple independent disease models, including induced pluripotent stem cell (iPSC)-derived neurons and skin fibroblasts from familial PD patients. Mutations in LRRK2 are the most frequent cause of PD. Intriguingly, we also identified the same mitochondrial impairments in sporadic PD patients. Thus, disrupted mitochondrial quality control may constitute a central component of PD pathogenesis. Remarkably, arresting mitochondrial motility by genetic manipulations in LRRK2G2019S iPSC-derived neurons restores mitochondrial quality control and rescues neurodegeneration. We therefore propose that therapeutic targeting of mitochondrial quality control may be broadly effective for multiple forms of PD, including sporadic cases.
Reporting Period:
Year 2
Mitochondria are a 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. It is not surprising that the impairment in this mitochondrial quality control system has been linked to Parkinson’s disease (PD), one of the most common neurodegenerative diseases. Based on our previous work that Parkinson’s associated proteins PINK1 and Parkin halt mitochondrial transport that might be essential for the damaged mitochondrial clearance, we hypothesized that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration, in the original application. For the past year, we have made substantial progress in achieving the specific aims. Briefly, using induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we have uncovered a defect in clearance of damaged mitochondria in PD. We have shown that in mutant cells the mitochondrial outer membrane protein Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and inhibiting mitochondrial degradation, in both familial and sporadic PD patients. Thus, impairment in Miro and mitochondrial quality control may constitute a central component of PD pathogenesis. Remarkably, partial reduction of Miro levels in human PD neuron and Drosophila PD models rescues neurodegeneration. We have revealed that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.
Reporting Period:
Year 3
Mitochondria are a 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. It is not surprising that the impairment in this mitochondrial quality control system has been linked to Parkinson’s disease (PD), one of the most common neurodegenerative diseases. Based on our previous work that Parkinson’s associated proteins PINK1 and Parkin halt mitochondrial transport that might be essential for the damaged mitochondrial clearance, we hypothesized that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration, in the original application. For the past year, we have made substantial progress in achieving the specific aims. Briefly, using induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we have uncovered a defect in clearance of damaged mitochondria in PD. We have shown that in mutant cells the mitochondrial outer membrane protein Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and inhibiting mitochondrial degradation, in both familial and sporadic PD patients. Thus, impairment in Miro and mitochondrial quality control may constitute a central component of PD pathogenesis. Remarkably, partial reduction of Miro levels in human PD neuron and Drosophila PD models rescues neurodegeneration. We have revealed that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.
Reporting Period:
Year 4 (NCE)
Mitochondria are a 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. It is not surprising that the impairment in this mitochondrial quality control system has been linked to Parkinson’s disease (PD), one of the most common neurodegenerative diseases. Based on our previous work that Parkinson’s associated proteins PINK1 and Parkin halt mitochondrial transport that might be essential for the damaged mitochondrial clearance, we hypothesized that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration, in the original application. For the past year, we have made substantial progress in achieving the specific aims. Briefly, using induced pluripotent stem cell (iPSC)-derived neurons from PD patients bearing mutations in SNCA, and other complementary models, we have uncovered a defect in clearance of damaged mitochondria in PD. We have shown that in mutant cells the mitochondrial outer membrane protein Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and inhibiting mitochondrial degradation. Thus, impairment in Miro and mitochondrial quality control may constitute a central component of PD pathogenesis. Remarkably, partial reduction of Miro levels in human PD neuron and Drosophila PD models rescues neurodegeneration. We have revealed that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.
Grant Application Details
Application Title:
Misregulated Mitophagy in Parkinsonian Neurodegeneration
Public Abstract:
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.
Statement of Benefit to California:
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.
