Mitochondrial Stress Modulates Elongator Protein 3 (ELP3) Function to Enhance Dopaminergic Neurotoxicity in Cell Culture and Animal Models of Parkinson's Disease

Abstract

Mitochondrial dysfunction is well established in Parkinson's disease (PD). Exposure to mitochondria‐targeting neurotoxicants, e.g., those neurotoxic pesticides that act as mitochondrial complex I inhibitors, has been linked to the pathogenesis of environmentally linked PD, but the molecular mechanisms underlying the enhanced vulnerability of dopaminergic neurons to mitochondrial toxicants are not fully understood. The histone acetyltransferase ELP3 (Elongator Protein 3) is the catalytic subunit of the RNA polymerase II elongator complex and plays an essential role in transcript elongation and maturation of projection neurons. Dysregulation of ELP3 has been implicated in a number of human disorders, but its potential role in the pathogenesis of PD remains elusive. In a serendipitous finding, we observed that mitochondria‐targeting pesticides can disrupt ELP3's function in dopaminergic neurons in cell culture and rodent models of PD. In this study, we further characterized ELP3 expression in the mouse brain and found high expression of full‐length ELP3 (62 kDa) in cytosolic fractions from different brain regions, while high levels of short‐form ELP3 (~40 kDa) were detected in the olfactory bulb (OB). Interestingly, immunohistochemical analyses revealed that ELP3 is highly expressed in TH‐positive neurons of the OB. Furthermore, OB slice cultures treated with the mitochondrial complex‐I inhibiting pesticide tebufenpyrad (Tebu) showed a reduced level of short‐form ELP3 in mitochondrial fractions. Consistently, we also found that ELP3 levels were significantly downregulated in the OB of transgenic MitoPark mice, a model which recapitulates mitochondrial dysfunction in PD. Collectively, our results indicate that ELP3 is a novel cellular target that can modulate the susceptibility of dopaminergic neurons to neurotoxic mitochondria‐targeting stressorsSupport or Funding InformationNIH grants ES026892 and ES027245 and Eugene and Linda Lloyd Endowed ChairThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.