Indicators of early neurodegeneration: gene-toxin interactions at the syanpse

DESCRIPTION (provided by applicant): Environmental risk factors as well as genetic predisposition underlie the development and progression of most neurodegenerative diseases. Although neuronal death characterizes the clinical stages of many of these diseases, dysfunction in the cell periphery, especially at the synapse, likely occur earlier. We find that environmental toxins such as pesticides that are implicated in Parkinson's disease (PD) rapidly affect synaptic transmission and synaptic plasticity. Many of these same toxins also affect the ubiquitin proteasome system (UPS), a major intracellular pathway for degradation of misfolded, oxidized or no-longer needed proteins. Further, several of the genes that have been linked to PD code for proteins involved in the UPS. In PD, the accumulation of protein aggregates in Lewy bodies points towards a deficit in protein processing and degradation. We therefore propose that proteasomal dysfunction in neurons compromises synaptic function and serves as an early indicator of neuronal degeneration. In addition to protein degradation, mitochondrial function appears compromised in PD. Interestingly, some PD-linked genes code for mitochondrial proteins and some pesticides linked to PD inhibit the mitochondrial electron transport chain. Compromised mitochondrial function will decrease cellular ATP levels and increases reactive oxygen species (ROS) and thus oxidized proteins. The UPS, which also degrades oxidized proteins, requires ATP for proper function. Thus, the UPS is a potential central target in the etiology of PD even for genes and toxins that directly affect mitochondrial function. We propose that changes in synaptic transmission triggered by UPS dysfunction represent an early indicator for neuronal vulnerability. Synaptic function thus offers a useful assay to test for the interaction between genetic and environmental factors underlying neurodegenerative diseases such as PD. PD is a progressive disease. Physiological alterations must precede clinical symptoms. Genetic animal models for PD similarly show progressive behavioral and physiological deficits and - like human disease - no deficits are evident early in life. Our studies will determine the impact of environmental toxins on synaptic transmission in neurons derived from PD animal models versus those from controls, and discern whether effects are more severe, occur at different concentrations or simply act in a different way. This work directly tests the interaction of genes and environmental factors in the etiology of PD. Our experiments are based on the hypothesis that genetic mutations found in neurodegenerative diseases interact with environmental toxins to affect synaptic function. We further propose synaptic dysfunction as an early sign of PD. Our experiments will lay the groundwork for identifying potential environmental and genetic risk factors for PD and other neurodegenerative diseases. The experimental paradigms developed will be useful in establishing a screening tool for the toxicity of pesticides and therapeutic interventions in relationship to neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Genetic predisposition and environmental factors underlie the development and progression of most neurodegenerative diseases such as Parkinson's disease (PD). This grant application proposes to test the hypothesis that communication between neurons at synapses is compromised by environmental toxins such as pesticides and that mutations in specific genes associated with PD interact with these very same pathways to exacerbate the synaptic dysfunction. The experiments are designed to elucidate this interaction between genes and the environment and to find support for the idea that alterations of synaptic function could be used in future studies as predictors of pesticide toxicity with respect to neurodegenerative diseases.

DESCRIPTION (provided by applicant): Environmental risk factors as well as genetic predisposition underlie the development and progression of most neurodegenerative diseases. Although neuronal death characterizes the clinical stages of many of these diseases, dysfunction in the cell periphery, especially at the synapse, likely occur earlier. We find that environmental toxins such as pesticides that are implicated in Parkinson's disease (PD) rapidly affect synaptic transmission and synaptic plasticity. Many of these same toxins also affect the ubiquitin proteasome system (UPS), a major intracellular pathway for degradation of misfolded, oxidized or no-longer needed proteins. Further, several of the genes that have been linked to PD code for proteins involved in the UPS. In PD, the accumulation of protein aggregates in Lewy bodies points towards a deficit in protein processing and degradation. We therefore propose that proteasomal dysfunction in neurons compromises synaptic function and serves as an early indicator of neuronal degeneration. In addition to protein degradation, mitochondrial function appears compromised in PD. Interestingly, some PD-linked genes code for mitochondrial proteins and some pesticides linked to PD inhibit the mitochondrial electron transport chain. Compromised mitochondrial function will decrease cellular ATP levels and increases reactive oxygen species (ROS) and thus oxidized proteins. The UPS, which also degrades oxidized proteins, requires ATP for proper function. Thus, the UPS is a potential central target in the etiology of PD even for genes and toxins that directly affect mitochondrial function. We propose that changes in synaptic transmission triggered by UPS dysfunction represent an early indicator for neuronal vulnerability. Synaptic function thus offers a useful assay to test for the interaction between genetic and environmental factors underlying neurodegenerative diseases such as PD. PD is a progressive disease. Physiological alterations must precede clinical symptoms. Genetic animal models for PD similarly show progressive behavioral and physiological deficits and - like human disease - no deficits are evident early in life. Our studies will determine the impact of environmental toxins on synaptic transmission in neurons derived from PD animal models versus those from controls, and discern whether effects are more severe, occur at different concentrations or simply act in a different way. This work directly tests the interaction of genes and environmental factors in the etiology of PD. Our experiments are based on the hypothesis that genetic mutations found in neurodegenerative diseases interact with environmental toxins to affect synaptic function. We further propose synaptic dysfunction as an early sign of PD. Our experiments will lay the groundwork for identifying potential environmental and genetic risk factors for PD and other neurodegenerative diseases. The experimental paradigms developed will be useful in establishing a screening tool for the toxicity of pesticides and therapeutic interventions in relationship to neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Genetic predisposition and environmental factors underlie the development and progression of most neurodegenerative diseases such as Parkinson's disease (PD). This grant application proposes to test the hypothesis that communication between neurons at synapses is compromised by environmental toxins such as pesticides and that mutations in specific genes associated with PD interact with these very same pathways to exacerbate the synaptic dysfunction. The experiments are designed to elucidate this interaction between genes and the environment and to find support for the idea that alterations of synaptic function could be used in future studies as predictors of pesticide toxicity with respect to neurodegenerative diseases.