Interactions Between Genetics, Protein, and Inflammation in Modeling Synucleinopathies
Abstract
Synucleinopathies, including Parkinson’s disease (PD), are a diverse group of neurodegenerative diseases without any disease modifying treatments. While the etiology of most cases of synucleinopathies, are idiopathic, it has been estimated that 5-10% of PD arises from known genetic mutations. The first mutations described that lead to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. In addition to genetic risk factors, exposure to environmental factors, including viral agents, has been shown to impart risk for developing synucleinopathies. The following studies describe multiple approaches to modeling synucleinopathies, including the use of various forms of α-syn, genetic mutation, and environmental agents. While striatal injection of oligomeric α-syn induced aggregation of α-syn, loss of substantia nigra dopaminergic neurons, and increased neuroinflammation in wild-type and α-syn mutant mice, mutant mice exhibited the same degree of neurodegeneration following monomeric α-syn. In a second set of experiments, we induced striatal expression of α-syn via Olig001-AlphaSYN, however this did not result in the neurodegeneration observed following injection of exogenous α-syn. We explored if a prior influenza infection could sensitize degeneration in this Olig001-AlphaSYN model of disease and found that no synergy occurred, and no nigrostriatal degeneration was observed. Finally, in another set of experiments combining a prior SARS-CoV-2 infection and a sublethal dose of a known parkinsonian toxin, we observed neurodegeneration only in groups previously exposed to viral infection, contrary to our influenza experiments. These results taken together highlight the importance of the origin and confirmation of α-syn, the role of the immune system, and neuroinflammation in modeling synucleinopathies. Not only do these results shed light on the pathogenesis of these complex and heterogenous diseases, but they also emphasize the need for continued expansion of experimental toolboxes and standardization across the field.
Subject Area
Neurosciences|Immunology|Genetics
Recommended Citation
Byrne, Matthew Daniel, "Interactions Between Genetics, Protein, and Inflammation in Modeling Synucleinopathies" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30488976.
https://jdc.jefferson.edu/dissertations/AAI30488976
