Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra.
Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.
Miller
Renee M
RM
Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, New York 14642, USA.
Callahan
Linda M
LM
Casaceli
Cindy
C
Chen
Linlin
L
Kiser
Gretchen L
GL
Chui
Buena
B
Kaysser-Kranich
Tamma M
TM
Sendera
Timothy J
TJ
Palaniappan
Chockalingam
C
Federoff
Howard J
HJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002908:Chronic Disease; D003599:Cytoskeleton / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010302:Parkinson Disease, Secondary / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology
D012333:RNA, Messenger; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine