The goal of the UCLA-CGEP is to investigate the hypothesis that the cellular mechanisms of action identifiedfor Putative Environmental Toxicants (PETs) contribute to a significant increase in PD risk; this project willfocus on investigations in rodents. Our group identified specific cellular mechanisms that are affected byPETs: the proteasome, microtubule integrity, and aldehyde dehydrogenase detoxification. Together withaltered VMAT function/expression that influences dopamine balance, these pathways-may affect thevulnerability of DA neurons to neurodegeneration. We propose to use our complementary expertise withmolecular, neurochemical, electrophysiological, and viral gene delivery approaches to determine whetherthese cellular mechanisms are affected by PETs in vivo in rodent brains and identify additional molecularand functional alterations induced by PETs that can contribute to increased vulnerability of DA neurons.Using PET treatment regimens that lead to mild dysfunction of DA neurons we will determine whether PETsalter levels of K48 and K63 ubiquination in tissue and increase levels of mitochondrial aldehydedehydrogenase substrates in DA neurons. We will identify new genes involved in the cellular mechanism ofactions of PETs by assessing transcriptome changes induced by PETs in nigrostriatal DA neurons isolatedby laser capture microdissection, and use slice electrophysiology to identify the mechanism of action ofPETs on the cellular properties of DA neurons. Finally, we will assess the role of regulation of DAcytoplasmic levels in modulating PET toxicity by examining the effects of virally or pharmacologically inducedalterations of VMAT in rats treated with PETs. These in vivo animal experiments will provide a link betweenmolecular mechanisms identified in projects 1 and 2 and the toxicity of compounds found by our group(Project 4) to increase PD risk in humans. In turn, the transcriptome and electropysiological analyses inProject 3 may point to new cellular pathways to be investigated in genetic studies in Drosophila (Project 2)and in humans (Project 4).
| Kusters, Cynthia D J; Paul, Kimberly C; Guella, Ilaria et al. (2018) Dopamine receptors and BDNF-haplotypes predict dyskinesia in Parkinson's disease. Parkinsonism Relat Disord 47:39-44 |
| Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2018) NFE2L2, PPARGC1?, and pesticides and Parkinson's disease risk and progression. Mech Ageing Dev 173:1-8 |
| Chen, Honglei; Ritz, Beate (2018) The Search for Environmental Causes of Parkinson's Disease: Moving Forward. J Parkinsons Dis 8:S9-S17 |
| Richter, Franziska; Subramaniam, Sudhakar R; Magen, Iddo et al. (2017) A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing ?-Synuclein. Neurotherapeutics 14:1107-1119 |
| Sanders, Laurie H; Paul, Kimberly C; Howlett, Evan H et al. (2017) Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk. Toxicol Sci 158:188-198 |
| Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7 |
| Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2017) Organophosphate pesticides and PON1 L55M in Parkinson's disease progression. Environ Int 107:75-81 |
| Chuang, Yu-Hsuan; Paul, Kimberly C; Bronstein, Jeff M et al. (2017) Parkinson's disease is associated with DNA methylation levels in human blood and saliva. Genome Med 9:76 |
| Richter, Franziska; Gabby, Lauryn; McDowell, Kimberly A et al. (2017) Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. Neurobiol Aging 51:54-66 |
| Narayan, Shilpa; Liew, Zeyan; Bronstein, Jeff M et al. (2017) Occupational pesticide use and Parkinson's disease in the Parkinson Environment Gene (PEG) study. Environ Int 107:266-273 |
Showing the most recent 10 out of 78 publications
