Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site-directed antisense gene therapy.
The levels of mRNA encoding the two isoforms of glutamic acid decarboxylase (GAD(65) and GAD(67)) were measured throughout the pallidal complex in normal and acutely (i.e., 1 month duration) and chronically (i.e., 5 years duration) parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated monkeys as well as in monkeys exposed to MPTP but asymptomatic for parkinsonism. GAD(65) mRNA labeling was modestly increased in the mid/caudal internal globus pallidus (GPi) but not in the external globus pallidus (GPe) in parkinsonian monkeys, compared with normal and asymptomatic monkeys. GAD(67) mRNA expression was highly increased in the mid/caudal GPi, and modestly increased in the GPe in parkinsonian monkeys compared with normal and asymptomatic animals. Infusion of GAD(67) antisense oligodeoxynucleotides bilaterally into the GPi resulted in a transient reversal of akinesia and bradykinesia that was not produced by infusion of missense oligodeoxynucleotides. These data emphasize the role of GAD enzyme (particularly GAD(67)) and GABA in the GPi for the expression of parkinsonian motor signs and suggest that selective manipulation of GABAergic neurotransmission in the GPi may have therapeutic potential for treating parkinsonism.
Schneider
Jay S
JS
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. jay.schneider@mail.tju.edu
Wade
Timothy V
TV
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005917:Globus Pallidus / Q000473:pathology*; D005968:Glutamate Decarboxylase / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics*; D008252:Macaca fascicularis; D008297:Male; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D012453:Saimiri
D007527:Isoenzymes; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2