Friday, April 19, 2024
4/19/2024
Abstract Chronic environmental exposure to neurotoxic concentrations of manganese (Mn) affects the basal ganglia system and has been linked to the etiology of Parkinsonism. Within basal ganglia (BG), Mn primarily accumulates in the globus pallidus and causes neuronal dysfunction in GABAergic neurons, resulting in dysregulation of the BG neural circuitry. Unlike Parkinson’s disease (PD), DAergic nuclei in the SN are not greatly affected by Mn neurotoxicity. Although Mn neurotoxicity manifests as extrapyramidal motor impairments, animal and human neurotoxicity studies indicate that it is also associated with various neuropsychiatric and cognitive disabilities. Several lines of evidence reveal olfactory deficits in humans following both occupational and environmental Mn exposure. Despite evidence linking olfactory dysfunction and BG pathology in Mn neurotoxicity, the underlying neurotoxicological mechanisms remain poorly understood. Recently, we reported that the neuropeptide prokineticin 2 (PK2) is rapidly upregulated in the early stages of DAergic neurotoxicity in a neurotoxin-induced animal model of Parkinsonism, and it participates in a novel compensatory protective response to counteract neurodegeneration by activating pro-survival pathways. We also obtained exciting new data showing a similar biphasic expression pattern for PK2 during Mn-induced neurotoxicity in vitro and in the SN and olfactory bulb (OB) regions, but not the striatum, of Mn-treated animals. Furthermore, our preliminary studies surprisingly identified that pharmacological stimulation of PK2 receptors or recombinant PK2 (rPK2) significantly upregulates the glial-derived neurotrophic factor (GDNF) expression and release in astrocytes both in vitro and in vivo. Additional preliminary results revealed a robust colocalization of PK2 and GDNF in OB. Thus, we hypothesize that disparity in the induction pattern of PK2-GDNF signaling in BG contributes to the differential vulnerability of GABAergic and DAergic neurons to Mn neurotoxicity. Also, Mn-induced impairment in PK2-GDNF signaling affects neurogenesis required for OB function and striatal neuronal survival. To fully establish the role of the PK2-GDNF axis in the BG and olfactory regions during Mn-induced neurotoxic insult, we will systematically pursue the following specific aims: (i) Map differential PK2 expression in BG, OB, subventricular zone (SVZ), and rostral migratory stream (RMS) regions and functionally correlate with neurogenesis, brain region-specific neuronal vulnerability and neurobehavioral deficits in mouse models of chronic Mn neurotoxicity; (ii) determine whether PK2 regulates GDNF levels and characterize the molecular mechanism of PK2 signaling in regulating GDNF in cell and animal models of Mn neurotoxicity; and (iii) evaluate the translational neuroprotective efficacy of novel PK2 receptor agonism and AAV-PK2/GDNF gene therapy in animal models of Mn neurotoxicity. Overall, we predict that our proposed studies will provide novel mechanistic insights into metal-induced BG and olfactory dysfunction and its role in the pathogenesis of environmentally linked Parkinsonism and will offer a novel therapeutic strategy.
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