Nurr1 repression mediates cardinal features of Parkinson's disease in α-synuclein transgenic mice
| Autor: | Maria Manousaki, Evangelos Sotiriou, Miquel Vila, Celine Perier, Maria Argyrofthalmidou, Athanasios D. Spathis, Demetrios K. Vassilatis, Zeta Papadopoulou-Daifoti, Amalia Poula, Ioanna Papapanagiotou, Pavlos Alexakos, Matina Maniati, Maira A Katsianou, Pothitos M. Pitychoutis, Leonidas Stefanis |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse AcademicSubjects/SCI01140 medicine.medical_specialty Parkinson's disease Mice Transgenic Biology Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine Mesencephalon Internal medicine Nuclear Receptor Subfamily 4 Group A Member 2 Genetics medicine Animals Molecular Biology Genetics (clinical) Neuroinflammation Dopaminergic Neurons Dopaminergic Heterozygote advantage Parkinson Disease General Medicine medicine.disease Phenotype 030104 developmental biology medicine.anatomical_structure Endocrinology alpha-Synuclein Neuron General Article 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 |
| Popis: | Duplication/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson’s disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)/Nurr1+/− (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. Aging ‘2-hit’ mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. Pathological abnormalities of phenotypic mice included SN neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. Mice with two wt Nurr1 alleles [ASYN(d)/Nurr1+/+] or with reduced ASYN load [ASYN(s)/Nurr1+/−] did not develop the phenotype or pathology. Critically, we found that aging ASYN(d), in contrast to ASYN(s), mice suppress Nurr1-protein levels in a brain region–specific manner, which in addition to Nurr1 hemizygosity is necessary to instigate PD pathogenesis. Our experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation. |
| Databáze: | OpenAIRE |
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