Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo.
Mitochondrial complex I inhibition has been implicated in the degeneration of midbrain dopaminergic (DA) neurons in Parkinson's disease. However, the mechanisms and pathways that determine the cellular fate of DA neurons downstream of the mitochondrial dysfunction have not been fully identified. We conducted cell-type specific gene array experiments with nigral DA neurons from rats treated with the complex I inhibitor, rotenone, at a dose that does not induce cell death. The genome wide screen identified transcriptional changes in multiple cell death related pathways that are indicative of a simultaneous activation of both degenerative and protective mechanisms. Quantitative PCR analyses of a subset of these genes in different neuronal populations of the basal ganglia revealed that some of the changes are specific for DA neurons, suggesting that these neurons are highly sensitive to rotenone. Our data provide insight into potentially defensive strategies of DA neurons against disease relevant insults.
Meurers
B H
BH
Department of Neurology, UCLA, Los Angeles, CA 90095, USA. bmeurers@mednet.ucla.edu
Zhu
C
C
Fernagut
P O
PO
Richter
F
F
Hsia
Y C
YC
Fleming
S M
SM
Oh
M
M
Elashoff
D
D
Dicarlo
C D
CD
Seaman
R L
RL
Chesselet
M F
MF
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005106:Exploratory Behavior / Q000187:drug effects; D015870:Gene Expression; D020869:Gene Expression Profiling; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D012333:RNA, Messenger; D012402:Rotenone; D005680:gamma-Aminobutyric Acid; D042967:Electron Transport Complex I; D004298:Dopamine