Neurotrophic factors are normally involved in the development and maintenance of the nigrostriatal system, yet they also possess incredible potential to repair it. Such trophic factors may have great potential as therapeutics in Parkinson's disease (PD) by providing long-term, lasting efficacy without the disabling side effects associated with current treatments. Our laboratory and others have revealed that the novel growth factor pleiotrophin (PTN) participates in the development and maintenance of the nigrostriatal system in a manner similar to glial cell line-derived neurotrophic factor (GDNF): 1) Both PTN and GDNF receptors are expressed by mesencephalic DA neurons;2) PTN and GDNF expression levels in the striatum peak during early postnatal development and decrease to low levels in adulthood;3) PTN and GDNF protein, mRNA and receptor expression in the striatum are upregulated in response to striatal denervation and;4) The addition of either PTN or GDNF to embryonic mesencephalic cultures specifically promotes tyrosine hydroxylase immunoreactive (THir) neuronal survival and neurite outgrowth. Such parallels suggest that PTN is an intrinsic factor critical to the development, maintenance and repair of the nigrostriatal DA system and point to its potential to provide neuroprotection and promote reconstruction of nigrostriatal circuitry when used as an exogenous therapeutic. This proposal will study the potential of PTN to provide neurorestoration in a rat model of PD, testing the hypothesis that overexpression of PTN in the adult rat nigrostriatal system can facilitate long-term functional recovery in a rat model of parkinsonism. Additional studies will examine whether PTN overexpression can improve dopamine graft survival and innervation of the denervated host striatum. Initially we will determine the peak levels of PTN expression in the nigrostriatal system of rats during development in order to identify the levels of PTN overexpression to be mediated by subsequent viral vector gene transfer. Our hypothesis then will be tested utilizing two separate approaches. First, we determine whether gene transfer of PTN to the striatum of rats with partial lesions can promote neurorestoration of the nigrostriatal system dopamine (DA) levels. Second, we will assess whether striatal PTN gene transfer can provide superior DA graft-mediated recovery in rats with complete unilateral lesions of the nigrostriatal system, including a decrease in the severity of levodopa-induced dyskinesias (LIDs). These studies will determine whether PTN gene transfer can be used as a therapeutic strategy to treat PD.
|Gombash, S E; Manfredsson, F P; Mandel, R J et al. (2014) Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways. Gene Ther 21:682-93|
|Gombash, Sara E; Manfredsson, Fredric P; Kemp, Christopher J et al. (2013) Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system. PLoS One 8:e81426|
|Gombash, Sara E; Lipton, Jack W; Collier, Timothy J et al. (2012) Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model. Mol Ther 20:544-54|