1. Heterozygous loss of Engrailed-1 and α-synucleinopathy (En1/SYN): A dual-hit preclinical mouse model of Parkinson's disease, analyzed with artificial intelligence.
- Author
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Stetzik L, Mercado G, Steiner JA, Lindquist A, Gilliland C, Schulz E, Meyerdirk L, Smith L, Molina J, and Moore DJ
- Subjects
- Animals, Male, Mice, Artificial Intelligence, Disease Models, Animal, Heterozygote, Mice, Inbred C57BL, Substantia Nigra metabolism, Substantia Nigra pathology, Substantia Nigra drug effects, Synucleinopathies pathology, Synucleinopathies metabolism, Synucleinopathies genetics, alpha-Synuclein metabolism, alpha-Synuclein genetics, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Parkinson Disease metabolism, Parkinson Disease pathology, Parkinson Disease genetics
- Abstract
In this study, we develop and validate a new Parkinson's disease (PD) mouse model that can be used to better understand how the disease progresses and to test the effects of new, potentially disease-modifying, PD therapies. Our central hypothesis is that mitochondrial dysfunction intercalates with misfolded α-synuclein (α-syn) accumulation in a vicious cycle, leading to the loss of nigral neurons. Our hypothesis builds on the concept that PD involves multiple molecular insults, including mitochondrial dysfunction and aberrant α-syn handling. We predicted that mitochondrial deficits, due to heterozygous loss of Engrailed-1 (En1+/-), combined with bilateral injections of pathogenic α-syn fibrils (PFFs), will act to generate a highly relevant PD model - the En1/SYN model. Here, En1+/- mice received bilateral intrastriatal stereotaxic injections of either PBS or α-syn fibrils and were analyzed using automated behavioral tests and deep learning-assisted histological analysis at 2, 4, and 6 months post-injection. We observed significant and progressive Lewy body-like inclusion pathology in the amygdala, motor cortex, and cingulate cortex, as well as the loss of tyrosine hydroxylase-positive (TH+) cells in the substantia nigra. The En1/SYN model also exhibited significant motor impairments at 6 months post-injection, which were however not exacerbated as we had expected. Still, this model has a comprehensive number of PD-like phenotypes and is therefore superior when compared to the α-syn PFF or En1+/- models alone., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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