Objective: To determine the link between α-syn accumulation and neuritic pathology in Parkinson’s Disease (PD).

Background: Neurological dysfunction in PD is highly associated with pathological deposits of aggregated α-syn in the brain. While mutations in the SNCA gene (α-syn) are causal in rare familial forms of PD, the prevalence of α-syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α-syn accumulation and disease pathogenesis.

Method: This study exploits stem cell technology to model PD using two human isogenic stem cell models of the disease. By employing a combination of human pluripotent stem cells (hPSCs) that harbor the SNCA-A53T mutation contrasted against isogenic controls and substantia nigra (SN) from PD patients, analyzed post-mortem, we evaluated the consequences of α-syn accumulation in human A9-type dopaminergic (DA) neurons (hNs).

Results: Using these systems, we have identified a mechanism whereby mutant α-syn inhibits the antioxidant response, that in-turn leads to axonal pathology through loss of expression of microtubule stabilizing proteins. Differentially expressed genes from both PD-patient SN and SNCA-A53T hNs were associated with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly, Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2-mediated gene expression and neuritic pathology. We show that SNCA-mutant hNs have deficits in neuritic length and complexity relative to controls as well as contorted axons with Tau positive varicosities. Furthermore, we show that mutant α-syn fails to complex with PKC, which in turn results in impaired activation of Nrf2. These neuritic defects result from impaired Nrf2-activity on Antioxidant Response Elements (AREs) localized to a microtubule associated protein (Map1b) gene enhancer and are rescued by both Nrf2 overexpression and pharmaceutical activation in PD neurons.

Conclusion: We show that reactivation of the Nrf2 pathway can rescue axonal neuropathology. This is the first demonstration of modulation of cytoskeletal elements as a potential therapy against PD, providing a previously unknown link between α-syn mutation and the antioxidant pathway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuritic-pathology-in-parkinsons-disease-results-from-loss-of-anti-oxidant-response-activity/