scholarly journals Spinal Cord Pathology in Alpha-Synuclein Transgenic Mice

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Sonja Mendritzki ◽  
Saskia Schmidt ◽  
Teresa Sczepan ◽  
Xin-Ran Zhu ◽  
Daniel Segelcke ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Spinal Cord ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transgenic Mice ◽  
Glial Cells ◽  
Alpha Synuclein ◽  
Motor Impairments ◽  
Neuron Death ◽  
Severe Motor

Accumulation ofα-synuclein is observed in neurodegenerative diseases like Parkinson's disease and Multiple System Atrophy. In previous studies with transgenic C57BL/6 mice overexpressingα-synuclein carrying the mutations A53T and A30P found in Parkinson's disease or with a parkin-null background, we reported severe mitochondrial impairments in neurons and to a larger extent in glial cells of the mesencephalon. Neuron death was not observed in the brain. Here we show that the mice show severe motor impairments in behavioral tests. In addition, these mice exhibit astrocytic cell death in the spinal cord, accompanied by extensive gliosis and microglial activation. This is shown by cell death staining and immunohistochemistry. Ultrastructural analyses revealed severe mitochondrial impairments not only in astrocytes, but also in oligodendrocytes and, to a small extent, in neurons. Thus, the transgenic mice show a profound pathology in glial cells of the spinal cord.

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 Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

2021 ◽  
Author(s):  
Qing Ye ◽  
Nasser Al-Kuwari ◽  
Pranay Srivast ◽  
Xiqun Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Glial Cells ◽  
Primary Cultures ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Braf V600e ◽  
Downstream Effectors ◽  
Mutational Activation

Abstract Background Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAFV600E as well as BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAFV600E-expressing microglia induced neuronal cell death. In neuronal cells, BRAFV600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

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

scholarly journals Alpha-synuclein promotes dopaminergic neuron death in Parkinson’s disease through microglial and NLRP3 activation

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Sarah Klein
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Inflammasome Activation ◽  
Neuron Death ◽  
Nlrp3 Inflammasome Activation

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that involves the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). After neuronal death, the subsequent reduction of dopamine levels in the brain induces motor deficits characteristic of this hypokinetic disorder. Although there is currently no known cause of PD, alpha-synuclein appears to have a prominent role in both microglial and NLRP3 inflammasome activation. The consequential release of the pro-inflammatory cytokine interleukin-1β (IL-1β) has been demonstrated to be responsible for neuroinflammation and neurodegeneration in PD. The present review highlights the role of alpha-synuclein aggregates in Parkinson’s disease pathogenesis. The PD alpha-synuclein preformed fibril (PFF) animal model permits the specific targeting of alpha-synuclein-mediated microglial and NLRP3 inflammasome activation in newly designed therapies. Studies using this model suggest MCC950 and its analogs as a potential new treatment to prevent neurodegeneration in Parkinson’s disease.

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.

Spinal cord stimulation improves forelimb use in an alpha-synuclein animal model of Parkinson's disease

2016 ◽  
Vol 127 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Ivani Brys ◽  
Wojciech Bobela ◽  
Bernard L. Schneider ◽  
Patrick Aebischer ◽  
Romulo Fuentes
Keyword(s):  
Parkinson’S Disease ◽  
Spinal Cord ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Spinal Cord Stimulation ◽  
Alpha Synuclein
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