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Nigral transcriptom...
Nigral transcriptomic profiles in Engrailed-1 hemizygous mouse models of Parkinson's disease reveal upregulation of oxidative phosphorylation-related genes associated with delayed dopaminergic neurodegeneration
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- Belfiori, Lautaro Francisco (author)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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- Dueñas Rey, Alfredo (author)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups,Ghent University Hospital,Ghent University
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- Ralbovszki, Dorottya Mária (author)
- Lund University
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- Jimenez-Ferrer, Itzia (author)
- Lund University
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- Fredlund, Filip (author)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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- Balikai, Sagar Shivayogi (author)
- Lund University
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- Ahrén, Dag (author)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Bioinformatik,Forskargrupper vid Lunds universitet,Molecular Cell Biology,Department of Biology,Faculty of Science,Bioinformatics,Lund University Research Groups,Science for Life Laboratory (SciLifeLab)
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- Brolin, Kajsa Atterling (author)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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- Swanberg, Maria (author)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: Frontiers in Aging Neuroscience. - 1663-4365. ; 16
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Abstract
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- INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder, increasing both in terms of prevalence and incidence. To date, only symptomatic treatment is available, highlighting the need to increase knowledge on disease etiology in order to develop new therapeutic strategies. Hemizygosity for the gene Engrailed-1 ( En1), encoding a conserved transcription factor essential for the programming, survival, and maintenance of midbrain dopaminergic neurons, leads to progressive nigrostriatal degeneration, motor impairment and depressive-like behavior in SwissOF1 (OF1 -En1 +/-). The neurodegenerative phenotype is, however, absent in C57Bl/6j (C57 -En1 +/-) mice. En1 +/- mice are thus highly relevant tools to identify genetic factors underlying PD susceptibility. METHODS: Transcriptome profiles were defined by RNAseq in microdissected substantia nigra from 1-week old OF1, OF1- En1 +/-, C57 and C57- En1 +/- male mice. Differentially expressed genes (DEGs) were analyzed for functional enrichment. Neurodegeneration was assessed in 4- and 16-week old mice by histology. RESULTS: Nigrostriatal neurodegeneration was manifested in OF1- En1 +/- mice by increased dopaminergic striatal axonal swellings from 4 to 16 weeks and decreased number of dopaminergic neurons in the SNpc at 16 weeks compared to OF1. In contrast, C57- En1 +/- mice had no significant increase in axonal swellings or cell loss in SNpc at 16 weeks. Transcriptomic analyses identified 198 DEGs between OF1- En1 +/- and OF1 mice but only 52 DEGs between C57- En1 +/- and C57 mice. Enrichment analysis of DEGs revealed that the neuroprotective phenotype of C57- En1 +/- mice was associated with a higher expression of oxidative phosphorylation-related genes compared to both C57 and OF1- En1 +/- mice. DISCUSSION: Our results suggest that increased expression of genes encoding mitochondrial proteins before the onset of neurodegeneration is associated with increased resistance to PD-like nigrostriatal neurodegeneration. This highlights the importance of genetic background in PD models, how different strains can be used to model clinical and sub-clinical pathologies and provides insights to gene expression mechanisms associated with PD susceptibility and progression.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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