Price DA, Martinex AA Seillier A, Koek W, Acosta Y, Fernandez E, Strong JR, Lutz B, Marsicano G, Roberts JL, and Giuffrida A. "WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease." Eur J Neurosci. 29:2177-86 (2009)
Cunningham RL, Giuffrida A, Roberts JL. "Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta." Endocrinology. 150:5539-48. (2009)
Khaing ZZ Roberts JL. "Embryonic mescencephalon derived neurospheres contain progenitors as well as differentiated neurons and glia." Restor Neurol Neurosci. 27:611-20 (2009).
The major research area in the Roberts' lab focuses on the role of growth factors 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 ERÎ± 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 estrogen's indirect neuroprotective effects on DA neurons. Pure astrocyte cultures were analyzed for membrane ERÎ± expression and signal transduction responses to 17Î²-estradiol (E2) treatment. ERÎ± 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 17Î²-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 factors, which includes BDNF, contributes significantly to the neuroprotection of DA neurons. Parallel studies are currently being performed using the rat N27 dopaminergic cell line to obtain a reproducible assay for neuroprotection.
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. It appears to be a direct mitochondrial effect the dopaminergic neurons as opposed to mediation via glia.
Integrative Biology II
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