Office: 210-567-8543
Email: robertsjl0@uthscsa.edu
The major research area in the Roberts’ lab focuses on the role of growth factors, cytokines, and estrogens in mediating protection/recovery of the brain from damage due to oxidative stress, focusing on the nigro-striatal pathway and its degeneration in Parkinson’s disease. This whole system is characterized from a perspective of the changes that occur as the animal's age progresses. Astrocytes, the largest cell population in the brain, regulate neuronal homeostasis and have been implicated in affecting the viability and functioning of surrounding neurons under stressed conditions. In addition, much attention has been focused on estrogen interactions in non-neuronal cell types. Recent data from our lab suggests indirect actions of estrogen through ERα and neighboring glia to protect dopamine neurons against MPP+ toxicity in mouse mesencephalic cultures. These results prompted us to study estrogen signaling in astrocytes to evaluate the mechanism of estrogens indirect neuroprotective effects on DA neurons. Pure astrocyte cultures were analyzed for membrane ERα expression and signal transduction responses to 17β-estradiol (E2) treatment. ERα was found to co-localize with the lipid raft marker, flotillan-1. E2 time course revealed a significant increase in Akt phosphorylation at 5-60 minutes. E2 also induced phosphorylation of the downstream transcription factor, CREB. These results were then analyzed in primary mesencephalic cultures in the presence of MPP+, which selectively damages DA neurons. Cultures treated with 17β-estradiol and the membrane impermeable estrogen, E2-BSA were both neuroprotective against MPP+ toxicity suggesting membrane-initiated neuroprotection. Inhibition of Akt blocked E2 induced neuroprotection, implicating the involvement of the PI3 kinase pathway. Finally, E2 conditioned media collected from pure astrocyte cultures rescued glial deficient mesencephalic cultures from MPP+. This study demonstrates that estrogen signaling through astrocytes and the release of soluble factor(s) contributes significantly to the neuroprotection of DA neurons. Proteomic analysis suggests that a GDNF family member, neurturin, is released into the media to elicit the protection.
These studies are currently being expanded to the negative effects of androgens in this neuroprotective paradigm possibly explaining the bias of this disorder to males. In another set of studies, we have cultured astroglia from young, middle-age and old mice and observed that the older astrocytes are less capable of protecting dopaminergic neurons from oxidative stress. We are currently performing proteomic analysis on the secreted factors to determine the molecular basis for these differences. Finally, the positive and negative role of immune cell invasion into the damaged nigro-striatal area is also being investigated in in vivo mouse models of PD.
My research group comprises Dr. Benxu Cheng, Assistant Professor; Yolanda Acosta, Research Associate; and Drs. Rebecca Cunningham & Elka Scordalakes, Postdoctoral Fellows.
Selected Publications
Price D, Daws LC, Owens WA, Gould GG, Frazer A, Roberts JL, and Giuffrida A. CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem. 101:389-396 (2007).
Bains M, Cousins JA, Roberts JL. Neuroprotection by estrogen against MPP+-induced dopamine neuron death is mediated by ER± in primary cultures of mouse mesencephalon. Experimental Neurology, 204:767-776 (2007).
Jeske NA, Berg KA, Cousins JC, Ferro ES, Clarke WP, Glucksman MJ, Roberts JL. Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia. J Neurochem. 97:13-21 (2006).
Wu TJ, Mani SK, Glucksman MJ, Roberts JL. Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5). Endocrinology. 146(1):280-6 (2005).
Jeske N, Glucksman MJ, and Roberts JL. Metalloendopeptidase EC3.4.24.15 is constitutively released from the exofacial leaflet of lipid rafts in neuronal GT1-7 cells. J Neurochemistry, 90(4):819-28 (2004).
