Abstract
Parkinson's disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Although current treatments provide only symptomatic relief, gene therapy has the potential to slow or halt the degeneration of nigrostriatal dopamine neurons in PD patients. Adeno-associated viruses (AAV) are vectors of choice in gene therapy because of their well-characterized safety and efficacy profiles; however, although gene therapy has been successful in preclinical models of the disease, clinical trials in humans have failed to demonstrate efficacy. Significantly, all primary AAV receptors of the virus are glycans. We thus hypothesize that age related changes in glycan receptors of heparan sulfate (HS) proteoglycans (receptor for rAAV2), and/or N-glycans with terminal galactose (receptor for rAAV9) results in poor adeno-associated virus binding in either the striatum or substantia nigra, or both, affecting transduction and gene delivery. To test our hypothesis we analyzed the striatum and substantia nigra for changes in HS, N-glycans and proteomic signatures in young versus aged rat brain striatum and substantia nigra. We observed different brain region-specific HS disaccharide profiles in aged compared with young adult rats for brain region-specific profiles in striatum versus substantia nigra. We observed brain region- and age-specific N-glycan compositional profiles with respect to the terminal galactose units that serve as receptors for AAV9. We also observed brain region-specific changes in protein expression in the aging nigrostriatal pathway. These studies provide insight into age- and brain region-specific changes in glycan receptors and proteome that will inform design of improved viral vectors for Parkinson Disease (PD) gene therapy.
Highlights
Parkinson’s disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain
Adeno-associated virus (AAV) vectors are being investigated in clinical trials to deliver trophic factors to the striatum of PD patients in order to provide neuroprotection for the remaining dopamine neurons [3]
Previous studies have demonstrated that transduction of the nigrostriatal system using AAV2, AAV5, or AAV9 is less efficient in aged rats than young adult rats [8, 10]
Summary
Parkinson’s disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Current treatments provide only symptomatic relief, gene therapy has the potential to slow or halt the degeneration of nigrostriatal dopamine neurons in PD patients. We observed brain region-specific changes in protein expression in the aging nigrostriatal pathway These studies provide insight into age- and brain region-specific changes in glycan receptors and proteome that will inform design of improved viral vectors for Parkinson Disease (PD) gene therapy. Adeno-associated virus (AAV) vectors are being investigated in clinical trials to deliver trophic factors to the striatum of PD patients in order to provide neuroprotection for the remaining dopamine neurons [3]. We sought to characterize the age-related changes in glycan and protein expression in the striatum and substantia nigra in young adult (3 months old) and aged (20 month old) rats. We applied glycosidase and protease enzymes in series to fresh-frozen striatum and substantia nigra
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call