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theses

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by motor dysfunction, eventual cognitive impairment and dementia in advanced stages. These symptoms arise as a result of decreased activity or death of dopaminergic (DA) neurons in the substantia nigra region of the brain, leading to dopamine depletion in the striatum disruption of neuronal circuitry in the basal ganglia. The current most common treatment for PD is levodopa, which can be converted into dopamine by surviving DA neurons, offering temporary relief of the motor dysfunction symptoms of PD. However, a key disadvantage of levodopa as a therapeutic strategy is that it does little to address the progression of PD and symptoms typically worsen as DA neurons continue to degenerate or die. Based on the a critical need for more comprehensive therapeutic approaches to PD that do more than relieve dopamine deficiency, but also disrupt the factors causing disease progression, the work in this dissertation focus on our efforts to address key aspects of Parkinson's disease pathology: neuronal degeneration, neuroinflammation, and synucleinopathy. To address neuronal degeneration, we investigated the potential for 3D fibrous synthetic substrates to support and transplant populations of human reprogrammed neurons into the brain. We found that fibrous substrate geometries could be tuned to shift reprogrammed cell populations towards either neuronal differentiation or maintenance of pluripotency. Microscale scaffolds generated from these fibrous substrates improved transplanted neuronal survival by at least an order of magnitude over traditional cell transplantation techniques. These proof-of-concept studies could be used to inform the future design of transplantable scaffolds supporting neurons reprogrammed to best address DA deficiency in PD. To address neuroinflammation and synucleinopathy, we examined the potential of microglia-targeting nanotherapeutics. We first identified scavenger receptors as a microglial receptor for α-synuclein (ASYN), a protein that forms characteristic protein aggregates and activates microglia in PD. We then designed nanoparticles targeting this interaction using synthetic amphiphilic scavenger receptor ligands. These amphiphilic molecules could reduce ASYN internalization and intracellular aggregation by microglia. We used nanoparticle constructs made using these synthetic ligands to target delivery of antioxidants to microglia, decreasing microglial activation in response to aggregated ASYN in vitro and in vivo. In summary, the studies described in this dissertation establish a valuable foundation for future therapeutic strategies addressing key features of PD pathophysiology and progression.

ETD_7609

Ph.D.

Includes bibliographical references

by Neal Kelsey Bennett

doi:10.7282/T3SF2ZGB

ETD doctoral

The author owns the copyright to this work.