JNK2 and JNK3 combined are essential for apoptosis in dopamine neurons of the substantia nigra, but are not required for axon degeneration.
Activation of c-jun N-terminal kinase (JNK) by the mitogen-activated protein kinase cascade has been shown to play an important role in the death of dopamine neurons of the substantia nigra, one of the principal neuronal populations affected in Parkinson's disease. However, it has remained unknown whether the JNK2 and JNK3 isoforms, either singly or in combination, are essential for apoptotic death, and, if so, the mechanisms involved. In addition, it has been unclear whether they play a role in axonal degeneration of these neurons in disease models. To address these issues we have examined the effect of single and double jnk2 and jnk3 null mutations on apoptosis in a highly destructive neurotoxin model, that induced by intrastriatal 6-hydroxydopamine. We find that homozygous jnk2/3 double null mutations result in a complete abrogation of apoptosis and a prolonged survival of the entire population of dopamine neurons. In spite of this complete protection at the cell soma level, there was no protection of axons. These studies provide a striking demonstration of the distinctiveness of the mechanisms that mediate cell soma and axon degeneration, and they illustrate the need to identify and target pathways of axon degeneration in the development of neuroprotective therapeutics.
Ries
Vincent
V
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Silva
Robert M
RM
Oo
Tinmarla F
TF
Cheng
Hsiao-Chun
HC
Rzhetskaya
Margarita
M
Kholodilov
Nikolai
N
Flavell
Richard A
RA
Kuan
Chia-Yi
CY
Rakic
Pasko
P
Burke
Robert E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000172:deficiency / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012183:Retrograde Degeneration / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D016622:Silver Staining / Q000379:methods; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects; D013565:Sympatholytics / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D013565:Sympatholytics; D051742:Transcription Factor CHOP; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D004298:Dopamine