Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l

Yan, Jieyu; Zhang, Pei; Jiao, Fengjuan; Wang, Qingzhi; He, Feng; Zhang, Qian; Zhang, Zheng; Lv, Ze-Xi; Peng, Xiang; Cai, Hongwei; Tian, Bo

doi:10.1371/journal.pone.0182092

Cited by 10 publications

(12 citation statements)

References 27 publications

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“…Mass spectrometry-based proteomics technologies have been widely used for the identification of proteins that are differentially expressed in disease animal models on a global scale. − To identify differentially expressed proteins, accurate quantification of protein levels is essential. Currently, multiple protein quantification approaches, such as label-free quantification, metabolic labeling, and isobaric mass tags are available .…”

Section: Discussionmentioning

confidence: 99%

“…The proteomic findings from various animal models of PD, such as the MPTP-treated mouse model, 6-OHDA-injected rat model, and A30P and A53T α-synuclein transgenic mouse models, have provided many valuable insights into several pathways that may be related to disease pathogenesis. − However, those proteomic analyses are limited because their proteome depths were shallow and the PD mouse models used did not sufficiently reflect the degeneration of DA neurons. Therefore, in-depth proteome analysis in mouse models that show visible PD-like phenotypes is required.…”

Section: Introductionmentioning

confidence: 99%

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Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson’s Disease

et al. 2021

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and, eventually, cognitive impairment. α-Synuclein protein is known as a central protein to the pathophysiology of PD, but the underlying pathological mechanism still remains to be elucidated. In an effort to understand how α-synuclein underlies the pathology of PD, various PD mouse models with α-synuclein overexpression have been developed. However, systemic analysis of the brain proteome of those mouse models is lacking. In this study, we established two mouse models of PD by injecting α-synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T α-synuclein to investigate common pathways in the two different types of the PD mouse models. For more accurate quantification of mouse brain proteome, the proteins were quantified using the method of stable isotope labeling with amino acids in mammals . We identified a total of 8355 proteins from the two mouse models; ∼6800 and ∼7200 proteins from α-synuclein PFF-injected mice and human A53T α-synuclein transgenic mice, respectively. Through pathway analysis of the differentially expressed proteins common to both PD mouse models, it was discovered that the complement and coagulation cascade pathways were enriched in the PD mice compared to control animals. Notably, a validation study demonstrated that complement component 3 (C3)-positive astrocytes were increased in the ventral midbrain of the intrastriatal α-synuclein PFF-injected mice and C3 secreted from astrocytes could induce the degeneration of dopaminergic neurons. This is the first study that highlights the significance of the complement and coagulation pathways in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson’s Disease

et al. 2021

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“…In this study, we conducted the proteome analysis of the ventral midbrain from two sophisticated mouse models of PD: -synuclein PFFs injection mouse model that represents sporadic PD (8) Mass spectrometry-based proteomics technologies have been widely used for the identification of proteins that are differentially expressed in disease animal models on a global scale (12)(13)(14)(15). To identify differentially expressed proteins, accurate quantifications of proteins are essential.…”

Section: Discussionmentioning

confidence: 99%

“…The proteomic findings from animal models of PD, such as MPTP-treated mouse model, 6-OHDA-injected rat model, and A30P*A53T α-synuclein transgenic mouse models, provided many valuable insights into several pathways that may be related to disease pathogenesis (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

Kim

Xiong

et al. 2020

Preprint

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Parkinson's disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and eventually, cognitive impairment. -Synuclein protein has been known to be the most culprit protein, but the underlying pathological mechanism still remains to be elucidated. As an effort to clarify the pathogenesis mechanism by -synuclein, various PD mouse models with -synuclein overexpression have been developed. However, the systemic analysis of protein abundance change by the overexpressed -synuclein in the whole proteome level has been still lacking. To address this issue, we established two sophisticated mouse models of PD by injecting -synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T synuclein to discover overlapping pathways, which could be altered in the two different types of PD mouse model. For more accurate quantification of mouse brain proteome, stable isotope labeling with amino acid in mammal-based quantification was implemented. As a result, we have successfully identified a total of 8,355 proteins from both of the mouse models; ~6,800 and ~7,200 proteins from -synuclein PFF injected mice and human A53T -synuclein transgenic mice, respectively. From the pathway analysis of the differentially expressed proteins in common, the complement and coagulation cascade pathway were determined as the most enriched ones. This is the first study that highlights the significance of the complement and coagulation pathway in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

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“…A quantitative proteomics study on the model expressing α-synuclein with both A30P and A53T mutations has also highlighted the role of mitochondrial dysfunction and oxidative stress in the substantia nigra, as well as impairment of the ubiquitin–proteasome system, and ER stress (Yan et al ., 2017). A useful data source was furthermore established by a detailed analysis of the protein levels in distinct regions of the mouse brain, which has been performed for both non-transgenic mice and the line 61 PD mouse model (Jung et al ., 2017 b ).…”

Section: Identification Of Biological Pathways Using In Vivo Modelsmentioning

confidence: 99%

Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

Sinnige

Stroobants

Dobson

et al. 2020

Quart. Rev. Biophys.

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Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.

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Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l

Cited by 10 publications

References 27 publications

Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson’s Disease

Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson’s Disease

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

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