Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1709-1725; doi:10.1093/hmg/ddi178
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Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection
1Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA, 2Harvard Center for Neurodegeneration and Repair, Boston, MA 02114, USA and 3Department of Environmental Medicine, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA
* To whom correspondence should be addressed. Tel: +1 6178553283; Fax: +1 6178553284; Email: isacson{at}hms.harvard.edu
Received April 1, 2005; Accepted May 2, 2005
Molecular differences between dopamine (DA) neurons may explain why the mesostriatal DA neurons in the A9 region preferentially degenerate in Parkinson's disease (PD) and toxic models, whereas 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 elevated in A10 DA neurons [>2-fold; false discovery rate (FDR) <1%]. Genes of interest for further functional analysis were selected by criteria of (i) fold differences in gene expression, (ii) real-time PCR validation and (iii) 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 three A10-elevated peptides (GRP, CGRP and PACAP) were further examined in both 
-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.
Present address: Department of Molecular and Life Science, Hanyang University, Korea
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