UC Irvine

Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α-synuclein into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α-synuclein in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. The wide array of cellular stress and symptoms related to over-abundance of α-synuclein makes DLB and other synucleinopathies challenging to treat. Many currently approved therapies fall short, suggesting that effective approaches will require the targeting of multiple mechanisms in order to treat motor, cognitive and other non-motor aspects of these diseases.

The goal of this dissertation is to determine the contributions of neural stem cell (NSC) transplantation to targeting multiple mechanisms related to α-synuclein over-expression in transgenic models of DLB. NSCs are an ideal candidate for transplantation due to their ability to migrate throughout a region of injury, and produce high levels of neurotrophins or growth factors critical to the survival and plasticity of neurons within the brain.

I have determined that mouse allogenic transplantation of NSCs lead to dramatic and sustained behavioral improvement in transgenic models of DLB. Critically, this improvement is dependent on NSC production of the neurotrophic factor, BDNF, which regulates downstream dopamine and glutamate neurotransmitter systems. Weighted Gene Co-Expression Network Analysis verified the involvement of multiple key networks at the transcriptome level, including neurotrophins, dopamine, glutamate and immune-modulating networks. In order to further investigate the therapeutic potential of this approach, I examined the contributions of human NSC (hNSC) xenotransplantation to improving these multiple mechanisms. I demonstrated that clinical-grade hNSCs also rescue motor and cognitive behavioral deficits in an immune-deficient DLB model, and that this improvement is sustained over time. Moreover, transplantation of hNSCs restored dopamine and glutamate systems through a non-BDNF dependent mechanism. Finally, in contrast to mouse NSCs, hNSCs likely achieve these behavioral and neurochemical benefits by altering α-synuclein conformers.