Publication Date
9-24-2024
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2406479121
PMID
39284050
PMCID
PMC11441490
PubMedCentral® Posted Date
9-16-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, alpha-Synuclein, Mice, Parkinson Disease, Gene Knock-In Techniques, Disease Models, Animal, Mice, Transgenic, Phosphorylation, Olfaction Disorders, Olfactory Bulb, Gastrointestinal Diseases, Enteric Nervous System, Humans, Male, alpha-Synuclein, G51D mutants, Parkinson’s disease, olfactory deficit, gastrointestinal dysfunction
Abstract
Many Parkinson’s disease (PD) models overexpress α-Synuclein using heterologous promoters, which is adequate to demonstrate that excessive α-Synuclein is toxic but not ideal for learning the precise ontogeny of the disease pathogenesis, specifically where the disease starts and how it progresses. To answer these questions, it is beneficial to generate a mouse model expressing a disease-causing mutation under the endogenous promoter. Here, we generated three Snca knock-in mice. Among them, homozygous SncaG51D mice develop motor deficits by 9 mo of age. These mice exhibit olfactory and gastrointestinal abnormalities by 6 mo. They lose dopaminergic neurons and have reduced dopamine at 18 mo, respectively. Their spatiotemporal pattern of phosphorylated alpha-Synuclein and progression of symptoms parallel those of human PD.
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