1. Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice.
- Author
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Kim Y, McInnes J, Kim J, Liang YHW, Veeraragavan S, Garza AR, Belfort BDW, Arenkiel B, Samaco R, and Zoghbi HY
- Subjects
- Animals, Mice, Mice, Transgenic, Phosphorylation, Olfaction Disorders genetics, Olfaction Disorders metabolism, Olfaction Disorders physiopathology, Olfactory Bulb metabolism, Olfactory Bulb pathology, Gastrointestinal Diseases genetics, Gastrointestinal Diseases metabolism, Gastrointestinal Diseases pathology, Enteric Nervous System metabolism, Enteric Nervous System physiopathology, Humans, Male, alpha-Synuclein metabolism, alpha-Synuclein genetics, Parkinson Disease genetics, Parkinson Disease metabolism, Parkinson Disease physiopathology, Parkinson Disease pathology, Gene Knock-In Techniques, Disease Models, Animal
- Abstract
Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA , which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The Snca
G51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies., Competing Interests: Competing interests statement:H.Y.Z. cofounded Cajal Neuroscience, is a Director of Regeneron Pharmaceuticals board, and is on the scientific advisory board of Cajal Neuroscience and the Column Group.- Published
- 2024
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