Quantitative Phosphoproteomic Analysis in Alpha-Synuclein Transgenic Mice Reveals the Involvement of Aberrant p25/Cdk5 Signaling in Early-stage Parkinson’s Disease

2020 ◽  
Vol 40 (6) ◽  
pp. 897-909 ◽  
Author(s):  
Feng He ◽  
Guangjian Qi ◽  
Qian Zhang ◽  
Hongwei Cai ◽  
Tongxia Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Early Stage ◽  
Alpha Synuclein

scholarly journals Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson’s disease

2018 ◽  
Vol 339 ◽  
pp. 153-168 ◽  
Author(s):  
Silke Frahm ◽  
Valeria Melis ◽  
David Horsley ◽  
Janet E. Rickard ◽  
Gernot Riedel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Alpha Synuclein

scholarly journals Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease

2019 ◽  
Author(s):  
LM Butkovich ◽  
MC Houser ◽  
T Chalermpalanupap ◽  
KA Porter-Stransky ◽  
AF Iannitelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Locus Coeruleus ◽  
Transgenic Mouse ◽  
Alpha Synuclein ◽  
Striatal Dopamine ◽  
Motor Symptoms ◽  
Age Dependent ◽  
Non Motor Symptoms

AbstractDegeneration of locus coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson’s disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter. These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine (DA) metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.Significance statementα-synuclein (asyn) pathology and loss of neurons in the locus coeruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson’s disease (PD). Dysregulated NE neurotransmission is associated with the non-motor symptoms of PD including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in non-motor behaviors without inclusions.

scholarly journals Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson’s disease-like phenotype

2022 ◽  
Author(s):  
Gaia Faustini ◽  
Francesca Longhena ◽  
Anna Masato ◽  
Valentina Bassareo ◽  
Roberto Frau ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Gene Silencing ◽  
Alpha Synuclein ◽  
Synapsin Iii

AAV2/DJ-mediated alpha-synuclein overexpression in the rat substantia nigra as early stage model of Parkinson’s disease

2019 ◽  
Vol 378 (1) ◽  
pp. 1-14
Author(s):  
Friederike Freiin von Hövel ◽  
Regina Rumpel ◽  
Andreas Ratzka ◽  
Dietmar Schreiner ◽  
Claudia Grothe
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Early Stage ◽  
Alpha Synuclein ◽  
Stage Model ◽  
Rat Substantia Nigra

scholarly journals 5-HT2AReceptor Binding in the Frontal Cortex of Parkinson’s Disease Patients and Alpha-Synuclein Overexpressing Mice: A Postmortem Study

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Nadja Bredo Rasmussen ◽  
Mikkel Vestergaard Olesen ◽  
Tomasz Brudek ◽  
Per Plenge ◽  
Anders Bue Klein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Executive Function ◽  
Transgenic Mice ◽  
Frontal Cortex ◽  
Receptor Binding ◽  
Alpha Synuclein ◽  
Association Cortex ◽  
Motor Disorder

The5-HT2Areceptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate5-HT2Areceptor binding levels in Parkinson’s brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with5-HT2Aalterations. Binding density for the5-HT2A-specific radioligand [3H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased5-HT2Areceptor binding in PD brains. In a separate study, we looked for changes in5-HT2Areceptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific5-HT2Areceptor binding measurements followed by gene expression analysis. The transgenic mice showed lower5-HT2Abinding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression.

scholarly journals Neuroinflammation in Parkinson's Disease and Related Disorders: A Lesson from Genetically Manipulated Mouse Models ofα-Synucleinopathies

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Kazunari Sekiyama ◽  
Shuei Sugama ◽  
Masayo Fujita ◽  
Akio Sekigawa ◽  
Yoshiki Takamatsu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Glial Cells ◽  
Genetic Modification ◽  
Early Stage ◽  
Related Model ◽  
Genetically Manipulated

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation inα-synuclein (αS) transgenic and related model mice. In the majority ofαS transgenic mice, astrogliosis was observed concomitantly with accumulation ofαS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results inαS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression.

scholarly journals Alpha-Synuclein as a Biomarker of Parkinson’s Disease: Good, but Not Good Enough

2021 ◽  
Vol 13 ◽  
Author(s):  
Upasana Ganguly ◽  
Sukhpal Singh ◽  
Soumya Pal ◽  
Suvarna Prasad ◽  
Bimal K. Agrawal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorders ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Motor Impairment ◽  
The Elderly ◽  
Alpha Synuclein ◽  
Cross Sectional ◽  
Peripheral Tissues

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.

scholarly journals Autophagy Inhibition and Inflammation Activation Induced by Phosphorylated Alpha-synuclein Through Toll-like Receptor 2 Pathway in the Hippocampus of MPTP Mouse Model of Parkinson’s Disease Contribute to Its Cognitive Function Decline in the Early Stage

2020 ◽  
Author(s):  
Ke-Zhong Zhang ◽  
Jing Wu ◽  
Wenwen Jiang ◽  
Ye Wang ◽  
Zhe Rong ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Function ◽  
Mouse Model ◽  
Early Stage ◽  
Alpha Synuclein ◽  
The Novel ◽  
Maze Test ◽  
Y Maze ◽  
Autophagy Inhibition

Abstract Background: To evaluate consecutively the cognitive function of a chronic mouse model of Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p) in different modeling periods, and to study the characteristics of cognitive decline in PD and its molecular mechanism.Methods: In this study, we used MPTP and probenecid to induce a chronic PD mouse model, the Y-maze test to evaluate the cognitive function of the model in different modeling periods, western blotting (WB) to quantify phosphorylated alpha-synuclein (p-α-syn), Toll-like receptors (TLRs), Nod-like receptors (NLRs), Choline acetyltransferase (ChAT), glial fibrillary acidic protein (GFAP), p62, Interleukin-1β (IL-1β) and other related indicators, immunohistochemical staining (IHC) to characterize the expression of p-α-syn, immunofluorescence staining (IF) to observe the co-localization of p-α-syn and cholinergic neurons (ChAT+) or astroglias (GFAP+) in the hippocampus. The TLR2 inhibitor CU-CPT22 was used to intervene in the subacute MPTP PD mouse model and then the expression of TLR2, ChAT, GFAP, p62 and IL-1β were evaluated again. Results: In the Y-maze test after 1/2/3/4/5 weeks of administration, the percentage of bouts to the Novel arm and the percentage of duration in the Novel arm of the MPTP/p group mice were lower than those of the Saline group mice, and there were statistical differences at the second week. At the same time, the p-α-syn monomer in the hippocampus of chronic MPTP/p PD mice increased, accompanied by the increase of GFAP, TLR2, Nuclear factor-κB (NF-κB), NLR pyrin domain containing 3 (NLRP3), p62 and IL-1β, and the decrease of the ratio of LC3Ⅱ to LC3I (LC3Ⅱ/I). The p-α-syn in the hippocampus increased, and co-localized significantly with GFAP and slightly with ChAT. TLR2 inhibitor CU-CPT22 can reduce the expression of GFAP, p62 and IL-1β in the subacute MPTP mouse model.Conclusion: Autophagy inhibition and inflammation activation induced by p-α-syn through TLR2 pathway in the hippocampus of MPTP mouse model of Parkinson’s disease contribute to its cognitive function decline in the early stage, indicating the potential of TLR2 as a therapeutic target for PD cognitive decline.

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