Correction of a rat model of Parkinson's disease by coexpression of tyrosine hydroxylase and aromatic amino acid decarboxylase from a helper virus-free herpes simplex virus type 1 vector.
We previously reported long-term biochemical and behavioral correction of the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD) by expression of tyrosine hydroxylase (TH) in the partially denervated striatum, using a herpes simplex virus type 1 (HSV-1) vector. This study had a number of limitations, including the use of a helper virus packaging system, limited long-term expression, and expression of only TH. To address these issues, we developed a helper virus-free packaging system, a modified neurofilament gene promoter that supports long-term expression in forebrain neurons, and a vector that coexpresses TH and aromatic amino acid decarboxylase (AADC). Coexpression of TH and AADC supported high-level (80%), behavioral correction of the 6-OHDA rat model of PD for 5 weeks. Biochemical correction included increases in extracellular dopamine and DOPAC concentrations between 2 and 4 months after gene transfer. Histologic analyses demonstrated neuronal-specific coexpression of TH and AADC at 4 days to 7 months after gene transfer, and cell counts revealed 1000 to 10,000 TH positive cells per rat at 2 months after gene transfer. This improved system efficiently corrects the rat model of PD.
Sun
Mei
M
Department of Neurology, West Roxbury VA Hospital/Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA.
Zhang
Guo-Rong
GR
Kong
Lingxin
L
Holmes
Courtney
C
Wang
Xiaodan
X
Zhang
Wei
W
Goldstein
David S
DS
Geller
Alfred I
AI
D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001522:Behavior, Animal; D002460:Cell Line; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019065:Virus Assembly
D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases