Mice deficient in group IV cytosolic phospholipase A2 are resistant to MPTP neurotoxicity.
Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytosolic form of phospholipase A2 (cPLA2) is regulated by changes in intracellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn-2 position of phospholipids. We examined the susceptibility of mice carrying a targeted mutation of the cPLA2 gene to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Mutant mice have no functional cPLA2 activity. Mice that were homozygous for the mutation (cPLA2-/-) were significantly resistant to MPTP-induced dopamine depletion as compared with littermate control (cPLA2+/+) and heterozygous mice (cPLA2+/-). These findings provide evidence that cPLA2 plays a role in MPTP neurotoxicity and suggest that cPLA2 may play a role in the development of Parkinson's disease in humans.
Klivenyi
P
P
Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston 02114, USA.
Beal
M F
MF
Ferrante
R J
RJ
Andreassen
O A
OA
Wermer
M
M
Chin
M R
MR
Bonventre
J V
JV
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D015259:Dopamine Agents / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D006719:Homovanillic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009498:Neurotoxins / Q000494:pharmacology*; D010741:Phospholipases A / Q000172:deficiency* / Q000235:genetics; D054467:Phospholipases A2; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D010741:Phospholipases A; D054467:Phospholipases A2; D015655:1-Methyl-4-phenylpyridinium; D006719:Homovanillic Acid