Matrix metalloproteinase-3 contributes to vulnerability of the nigral dopaminergic neurons.
Dopamine(DA)rgic neurons are particularly vulnerable due to the presence of oxidative stress-inducing molecules such as DA, tetrahydrobiopterin, iron and tyrosine hydroxylase (TH). We have recently observed that matrix metalloproteinase-3 (MMP-3) is involved in degeneration of DArgic neurons. In the present study, we sought to explore the role of MMP-3 in DArgic neurons not exposed to apparent stress conditions. In 8-week-old male mice deficient of MMP-3 gene (MMP-3 KO), the total number of DArgic neurons in the substantia nigra was considerably higher than wild type (WT). Primary cultured mesencephalic neurons from MMP-3 KO showed higher [(3)H]DA uptake capability compared to that of WT. The number of TH-immunopositive neurons and the length of average dendritic branch were also greater. This appeared to be selective for the DArgic system, because [(3)H]GABA uptake and calbindin D-28K and MAP-2 immunoreactivities were unaltered. On the other hand, no differences were noted in the levels of the striatal DA, DOPAC and BH4 and TH protein between the KO and WT. Interestingly, TH immunodensity per cell was lower in the DArgic neurons of MMP-3 KO both in primary culture and in vivo, suggesting the presence of a compensatory mechanism. These results further indicate a role of MMP-3 in the demise of DArgic neurons and suggest MMP-3 as a candidate cellular target for neuroprotective therapy.
Kim
Sung Tae
ST
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
Kim
Eun-Mee
EM
Choi
Ji Hyun
JH
Son
Hyo Jin
HJ
Ji
In Jung
IJ
Joh
Tong H
TH
Chung
Sun Ju
SJ
Hwang
Onyou
O
D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D003712:Dendrites / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D013378:Substantia Nigra / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D019278:Matrix Metalloproteinase 3; D004298:Dopamine