Glycomic and Proteomic Changes in Aging Brain Nigrostriatal Pathway
| Autor: | Kshitij Khatri, Chun Shao, Nicole K. Polinski, Joseph Zaia, Rekha Raghunathan, Deborah R. Leon, Fredric P. Manfredsson, Mark E. McComb, Joshua A. Klein, John D. Hogan, Caryl E. Sortwell |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Proteomics 0301 basic medicine Aging Parkinson's disease Proteome Nigrostriatal pathway Substantia nigra Striatum Gene delivery Biology Pharmacology Disaccharides Biochemistry Analytical Chemistry 03 medical and health sciences 0302 clinical medicine Polysaccharides medicine Animals Aging brain Glycomics Molecular Biology Research Dopaminergic Galactose medicine.disease Symptomatic relief Corpus Striatum Rats Inbred F344 Substantia Nigra 030104 developmental biology medicine.anatomical_structure nervous system Organ Specificity Heparitin Sulfate 030217 neurology & neurosurgery |
| Zdroj: | Molecular & Cellular Proteomics. 17:1778-1787 |
| ISSN: | 1535-9476 |
| DOI: | 10.1074/mcp.ra118.000680 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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