Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi178
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1 Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478; Harvard Center for Neurodegeneration and Repair, Boston, MA 02114
* To whom correspondence should be addressed. Molecular differences between dopamine (DA) neurons may explain why in Parkinson's disease (PD) and toxic models, the mesostriatal DA neurons in the A9 region preferentially degenerate, while the adjacent A10 region mesolimbic and mesocortical DA neurons are relatively spared. To characterize innate physiological differences between A9 and A10 DA neurons, we determined gene expression profiles in these neurons in the adult mouse by laser capture microdissection, microarray analysis and real time PCR. We found 42 genes relatively elevated in A9 DA neurons, whereas 61 genes were more expressed in A10 DA neurons (> 2 fold; false discovery rate [FDR] < 1 %). Genes of interest for further functional analysis were selected by criteria of (1) fold differences in gene expression, (2) real time PCR validation and (3) potential roles in neurotoxic or protective biochemical pathways. Three A9-elevated molecules (G-protein coupled inwardly rectifying K channel 2 [GIRK2], adenine nucleotide translocator 2 [ANT-2], and the growth factor IGF-1) and 3 A10-elevated peptides (GRP, CGRP and PACAP) were further examined in both
Received April 1, 2005
Revised April 28, 2005
Accepted April 28, 2005
Article
Cell type specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection
2 Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478
3 Department of Environmental Medicine, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642
Ole Isacson, E-mail: isacson{at}hms.harvard.edu
Abstract 
-synuclein overexpressing PC12 (PC12-Syn) cells and rat primary ventral mesencephalic (VM) cultures exposed to MPP+ neurotoxicity. GIRK2-positive DA neurons were more vulnerable to MPP+ toxicity and overexpression of GIRK2 increased the vulnerability of PC12-Syn cells to the toxin. Blocking of ANT decreased vulnerability to MPP+ in both cell culture systems. Exposing cells to IGF-1, GRP and PACAP decreased vulnerability of both cell types to MPP+, whereas CGRP protected PC12-Syn cells but not primary VM DA neurons. These results indicate that certain differentially expressed molecules in A9 and A10 DA neurons may play key roles in their relative vulnerability to toxins and PD.
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