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Nitric oxide-mediated neurite retraction is induced by aberrant α-synuclein deposition in Parkinson’s disease

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Title: Nitric oxide-mediated neurite retraction is induced by aberrant α-synuclein deposition in Parkinson’s disease
Author: Czaniecki, Chris
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Ryan, Scott
Abstract: Parkinson’s Disease (PD) is a neurodegenerative disorder associated with pathological deposits of aggregated α-synuclein in multiple brain regions. While motor dysfunction is a primary phenotype of PD, many patients develop symptoms of cognitive impairment, including dementia. PD dementia is highly associated with pathological deposits of aggregated α-synuclein in neurites. In addition, an early marker of neurodegeneration is the retraction of synaptic terminals and distal axons of neurons, which usually precedes cell death. However, it is unclear if neurite retraction in PD is an early marker of pathology, or is consequence to global neuronal cell death. To investigate these questions, a hESC model of PD was utilized which incorporates the A53T α-synuclein mutation. This system allows for comparison of A53T α-synuclein mutant cells against isogenic controls. Following differentiation to dopaminergic (DA) neurons, it was determined that A53T DA neurons display a global decrease in neurite length and complexity. Interestingly, the addition of preformed α-synuclein fibrils on WT DA neurons evoked a similar retraction of neurite branching. Treatment with L-NAME, a nitric oxide synthase inhibitor, was able to rescue neurite morphology in A53T DA neurons, suggesting a causal link to nitrosative stress. Furthermore, induction of the anti-oxidant response via NRF2 activation attenuated neurite retraction. Overall, this is the first evidence suggesting a link between α-synuclein aggregation and neurite retraction in a human PD model system. More importantly, detoxifying neurons of redox stress through forced activation of NRF2 may provide a new therapeutic avenue against PD.
URI: http://hdl.handle.net/10214/10122
Date: 2016-11
Rights: Attribution-NoDerivs 2.5 Canada
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Attribution-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NoDerivs 2.5 Canada