Impact of Pleiotrophin Gene Therapy in 6-hydroxydopamine and AAV Alpha-synuclein Rodent Models of Parkinson's Disease.

摘要

Trophic factor gene therapy to slow nigral dopamine (DA) neuron degeneration in Parkinson's disease (PD) has been extensively tested in preclinical animal models. Despite encouraging results in toxin based PD models, no neurotrophic factor therapy to date has yielded clinical benefits, indicating the continued need for new candidates and new targets. The studies in this dissertation were designed to investigate the therapeutic potential of the trophic factor pleiotrophin (PTN). PTN promotes survival and outgrowth of mesencephalic DA producing neurons in vitro and is upregulated in the substantia nigra (SN) of PD patients. This dissertation includes a series of studies investigating the effects of nigrostriatal PTN overexpression by injection of recombinant adeno-associated viral vectors (rAAV) in both the 6-hydroxydopamine (6-OHDA) and human wild-type alpha-synuclein (α-syn) overexpression (AAV) rat models of PD. Results from these studies reveal that intrastriatal PTN overexpression prior to 6-OHDA insult is neuroprotective for dopaminergic neurons of the substantia nigra pars compacta (SNpc) and to DA projections to the striatum, and provides restoration of motor performance. Furthermore, only PTN overexpression targeted to the striatum specifically results in long-term nigrostriatal sparing, whereas PTN co-transduction of the SN mitigates long-term neuroprotection. In contrast, PTN overexpression in the nigrostriatal system is unable to protect SN DA neurons or striatal terminals from α-syn aggregation and toxicity and is unable to ameliorate α-syn-induced motor deficits. Taken together, these results suggest that PTN overexpression is protective against oxidative stress mechanisms of neurodegeneration, but is ineffective against the α-syn overexpression-induced toxicity produced in the AAV-α-syn model. It is unclear whether these findings signal PTN gene therapy failure or AAV-α-syn model limitations. Whether the 6-OHDA, the AAV-α-syn model or neither possess predictive validity for neuroprotection in the PD remains to be determined. Further investigation of the survival signaling induced by PTN in the face of 6-OHDA and the determination of whether this signaling is absent in conditions of α-syn overexpression.