The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease.
The mechanisms leading to degeneration of dopaminergic neurons (DNs) in the substantia nigra of patients with Parkinson's disease (PD) are not completely understood. Here, we show, in the postmortem human tissue, that these neurons aberrantly express mitosis-associated proteins, including the E2F-1 transcription factor, and appear to duplicate their nuclear DNA. We further demonstrate that the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injected into mice and application of its active metabolite 1-methyl-4-phenylpyridinium to mesencephalic cultures activate the retinoblastoma-E2F pathway in postmitotic DNs. We also find that cell death rather than mitotic division followed the toxin-induced replication of DNA, as determined by BrdU incorporation in DNs. In addition, blocking E2F-1 transcription protected cultured DNs against 1-methyl-4-phenylpyridinium toxicity. Finally, E2F-1-deficient mice were significantly more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic cell death than their wild-type littermates. Altogether, BrdU incorporation in mature neurons and lack of evidence for newborn neurons argue against neuronal turnover in normal conditions or during pathological states in the substantia nigra. Instead, our results demonstrate that mitosis-like signals are activated in mature DNs in patients with PD and mediate neuronal death in experimental models of the disease. Inhibition of mitosis-like signals may therefore provide strategies for neuroprotection in PD.
Höglinger
Günter U
GU
Department of Experimental Neurology, Philipps University, 35039 Marburg, Germany.
Breunig
Joshua J
JJ
Depboylu
Candan
C
Rouaux
Caroline
C
Michel
Patrick P
PP
Alvarez-Fischer
Daniel
D
Boutillier
Anne-Laurence
AL
Degregori
James
J
Oertel
Wolfgang H
WH
Rakic
Pasko
P
Hirsch
Etienne C
EC
Hunot
Stéphane
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010300:Parkinson Disease / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D013378:Substantia Nigra / Q000378:metabolism*
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016376:Oligonucleotides, Antisense; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium