Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model.
Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult.
Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.
Sara E
SE
Gombash
Jack W
JW
Lipton
Timothy J
TJ
Collier
Lalitha
L
Madhavan
Kathy
K
Steece-Collier
Allyson
A
Cole-Strauss
Brian T
BT
Terpstra
Anne L
AL
Spieles-Engemann
Brian F
BF
Daley
Susan L
SL
Wohlgenant
Valerie B
VB
Thompson
Fredric P
FP
Manfredsson
Ronald J
RJ
Mandel
Caryl E
CE
Sortwell
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin; D016627:Oxidopamine