Dataset Information

Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. However, its cellular and molecular mechanisms still wrap in the mist. This is partially caused by the absence of appropriate animal models mimicking sporadic PD that constitutes the majority of cases. Previously, we reported that a cysteine protease, asparagine endopeptidase (AEP), is activated in an age-dependent manner, and cleaves α-synuclein in the brain of sporadic PD patients. The AEP-derived α-synuclein 1-103 fragment is required for the pathogenesis of PD. Thus, we designed and characterized a novel transgenic mouse line expressing α-synuclein 1-103 (designated N103 mice). This model shows an abundant accumulation of pathological α-synuclein in the central nervous system, loss of dopaminergic neurons in the substantia nigra, and progressive striatal synaptic degeneration. The N103 mice also manifest age-dependent PD-like behavioral impairments. Notably, the mice show weight loss and constipation, which are the common non-motor symptoms in PD. The RNA-sequencing analysis found that the transcriptomics pattern was extensively altered in N103 mice. In conclusion, the N103 mouse line, as a brand-new tool, might provide new insights into PD research.

SUBMITTER: Tian Y

PROVIDER: S-EPMC8569470 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson's Disease.

Tian Ye Y He Mingyang M Pan Lina L Yuan Xin X Xiong Min M Meng Lanxia L Yao Zhaohui Z Yu Zhui Z Ye Keqiang K Zhang Zhentao Z

Frontiers in aging neuroscience 20211022

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. However, its cellular and molecular mechanisms still wrap in the mist. This is partially caused by the absence of appropriate animal models mimicking sporadic PD that constitutes the majority of cases. Previously, we reported that a cysteine protease, asparagine endopeptidase (AEP), is activated in an age-dependent manner, and cleaves α-synuclein in the brain of sporadic PD patients. The AEP-derived α-synuclein 1-103 ...[more]

PMID: 34744697

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Project description:BackgroundLoss of substantia nigra dopaminergic cells and alpha-synuclein (α-syn)-rich intraneuronal deposits within the central nervous system are key hallmarks of Parkinson's disease (PD). Levodopa (L-DOPA) is the current gold-standard treatment for PD. This study aimed to evaluate in vivo retinal changes in a transgenic PD model of α-syn overexpression and the effect of acute levodopa (L-DOPA) treatment.MethodsAnaesthetised 6-month-old mice expressing human A53T alpha-synuclein (HOM) and wildtype (WT) control littermates were intraperitoneally given 20 mg/kg L-DOPA (50 mg levodopa, 2.5 mg benserazide) or vehicle saline (n = 11-18 per group). In vivo retinal function (dark-adapted full-field ERG) and structure (optical coherence tomography, OCT) were recorded before and after drug treatment for 30 min. Ex vivo immunohistochemistry (IHC) on flat-mounted retina was conducted to assess tyrosine hydroxylase (TH) positive cell counts (n = 7-8 per group).ResultsWe found that photoreceptor (a-wave) and bipolar cell (b-wave) ERG responses (p < 0.01) in A53T HOM mice treated with L-DOPA grew in amplitude more (47 ± 9%) than WT mice (16 ± 9%) treated with L-DOPA, which was similar to the vehicle group (A53T HOM 25 ± 9%; WT 19 ± 7%). While outer retinal thinning (outer nuclear layer, ONL, and outer plexiform layer, OPL) was confirmed in A53T HOM mice (p < 0.01), L-DOPA did not have an ameliorative effect on retinal layer thickness. These findings were observed in the absence of changes to the number of TH-positive amacrine cells across experiment groups. Acute L-DOPA treatment transiently improves visual dysfunction caused by abnormal alpha-synuclein accumulation.ConclusionsThese findings deepen our understanding of dopamine and alpha-synuclein interactions in the retina and provide a high-throughput preclinical framework, primed for translation, through which novel therapeutic compounds can be objectively screened and assessed for fast-tracking PD drug discovery.

Project description:α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.

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Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson's Disease.

Publications

Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson's Disease.

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