scholarly journals Models of multiple system atrophy

2019 ◽  
Vol 51 (11) ◽  
pp. 1-10 ◽  
Author(s):  
He-Jin Lee ◽  
Diadem Ricarte ◽  
Darlene Ortiz ◽  
Seung-Jae Lee
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Mouse Models ◽  
Clinical Manifestations ◽  
Lewy Bodies ◽  
Model Systems ◽  
Future Research ◽  
Cytoplasmic Inclusions ◽  
Cellular Models ◽  
Brain Extracts

AbstractMultiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the α-synucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis. Studies on MSA pathogenesis are scarce relative to studies on the pathogenesis of other synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies. However, recent developments in cellular and animal models of MSA, especially α-synuclein transgenic models, have driven advancements in research on this disease. Here, we review the currently available models of MSA, which include toxicant-induced animal models, α-synuclein-overexpressing cellular models, and mouse models that express α-synuclein specifically in oligodendrocytes through cell type-specific promoters. We will also discuss the results of studies in recently developed transmission mouse models, into which MSA brain extracts were intracerebrally injected. By reviewing the findings obtained from these model systems, we will discuss what we have learned about the disease and describe the strengths and limitations of the models, thereby ultimately providing direction for the design of better models and future research.

scholarly journals Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ethan W. Hass ◽  
Zachary A. Sorrentino ◽  
Grace M. Lloyd ◽  
Nikolaus R. McFarland ◽  
Stefan Prokop ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Biochemical Properties ◽  
Detection Methods ◽  
Inferior Olivary Nucleus ◽  
Cytoplasmic Inclusions ◽  
Neuronal Populations ◽  
Carboxy Terminal Region ◽  
High Level ◽  
Carboxy Terminal

AbstractMultiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA.

scholarly journals Autophagy in α-Synucleinopathies—An Overstrained System

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3143
Author(s):  
Lisa Fellner ◽  
Elisa Gabassi ◽  
Johannes Haybaeck ◽  
Frank Edenhofer
Keyword(s):  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Trigger Point ◽  
Lewy Bodies ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Inclusion Formation ◽  
Intracytoplasmic Inclusion ◽  
Current Review ◽  
Disease Initiation

Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.

scholarly journals Is Multiple System Atrophy a Prion-like Disorder?

2021 ◽  
Vol 22 (18) ◽  
pp. 10093
Author(s):  
Kurt A. Jellinger ◽  
Gregor K. Wenning ◽  
Nadia Stefanova
Keyword(s):  
Multiple System Atrophy ◽  
Prion Disease ◽  
Scientific Evidence ◽  
Motor Impairment ◽  
Lewy Bodies ◽  
Convincing Evidence ◽  
Cytoplasmic Inclusions ◽  
Primary Astrocyte ◽  
Disease Causation ◽  
Human Brains

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson’s disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the “prion-like” transfer of “strains” of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as “prions”, “prion-like”, “prionoids”, or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.

scholarly journals Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy

2019 ◽  
Vol 78 (10) ◽  
pp. 877-890 ◽  
Author(s):  
Norihito Uemura ◽  
Maiko T Uemura ◽  
Angela Lo ◽  
Fares Bassil ◽  
Bin Zhang ◽  
...  
Keyword(s):  
White Matter ◽  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Mouse Models ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Wild Type ◽  
Time Points ◽  
Progressive Accumulation

Abstract Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (α-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial α-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic α-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal α-Syn aggregates and the subsequent interneuronal transmission of α-Syn aggregates. However, injections of α-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial α-Syn aggregates, raising questions about the pathogenesis of oligodendroglial α-Syn aggregates in MSA. Here, we report that WT mice injected with mouse α-Syn (m-α-Syn) PFFs develop neuronal α-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial α-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial α-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-α-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial α-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial α-Syn aggregation in MSA.

scholarly journals Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and multiple system atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Therése Klingstedt ◽  
Bernardino Ghetti ◽  
Janice L. Holton ◽  
Helen Ling ◽  
K. Peter R. Nilsson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Fluorescence Lifetime Imaging ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Lewy Pathology ◽  
Lifetime Imaging ◽  
The Difference

AbstractSynucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and multiple system atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for multiple system atrophy. The inclusions of Parkinson’s disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and multiple system atrophy.

scholarly journals Clinical Manifestations of Parkinson's Disease and Parkinsonism

2003 ◽  
Vol 30 (S1) ◽  
pp. S2-S9 ◽  
Author(s):  
Doug Everett Hobson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differential Diagnosis ◽  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Clinical Manifestations ◽  
Lewy Bodies ◽  
Accurate Diagnosis ◽  
Additional Information ◽  
Diagnosis And Prognosis

The most common disorder in a patient presenting to a movement disorder clinic will be parkinsonism. The challenge is to provide the patient with the most accurate diagnosis and prognosis possible. The assumption at the time of initial presentation of the clinical diagnosis of Parkinson's disease is often wrong (20-25%). Waiting to see the pattern of progression, and response to medication provides invaluable additional information. This manuscript summarizes the clinical manifestations of Parkinson's disease and the main akinetic-rigid syndromes (progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degeneration, and dementia with Lewy bodies) that make up the differential diagnosis.

Controversies in the Management of Mycobacterium Avium Complex Infection in AIDS Patients

1993 ◽  
Vol 27 (7-8) ◽  
pp. 928-937 ◽  
Author(s):  
Charles A. Peloquin
Keyword(s):  
Mouse Models ◽  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Susceptibility Testing ◽  
Traditional Approach ◽  
Clinical Manifestations ◽  
Future Research ◽  
General Description ◽  
Aids Patients

OBJECTIVE: To update readers on the clinical management of infections secondary to Mycobacterium avium complex (MAC) in patients with AIDS. A general description of the organism, culture and susceptibility testing, and clinical manifestations of the disease is provided. Several aspects of the treatment of the disease, including an historical perspective, current approaches, and future research opportunities, are described. DATA SOURCES: Current medical literature, including abstracts presented at international meetings, is reviewed. References were identified through MEDLINE, Current Contents, and published meeting abstracts. STUDY SELECTION: Data regarding the epidemiology, clinical manifestations, culture and susceptibility testing, and treatment of MAC are cited. Specific attention is given to the management of patients with MAC infection. DATA EXTRACTION: Information contributing to the discussion of the topics selected by the author is reviewed. Data supporting and disputing specific conclusions are presented. DATA SYNTHESIS: Disseminated MAC infection is diagnosed antemortem in approximately 30 percent of patients with AIDS; postmortem rates of isolation exceed 50 percent. The incidence of MAC may increase as attempts at isolating the organism become more aggressive. The traditional approach to the isolation, susceptibility testing, and treatment of MAC has been derived from the management of Mycobacterium tuberculosis, with disappointing results. Newer radiometric in vitro methods of susceptibility testing appear to show more promise. Current mouse models of MAC are not true AIDS models; new CD4-deficient mouse models are being developed. Clinical mycobacteriologic and pharmacokinetic laboratory support have been underused, with treatment generally proceeding empirically. New agents that may contribute to the management of disseminated MAC infection include the macrolide derivatives clarithromycin and azithromycin. Research also continues with new rifamycins (including rifabutin) and fluoroquinolones (ciprofloxacin, sparfloxacin). Preliminary results suggest a central role for macrolides in the treatment of disseminated MAC; effective companion drugs are needed to prevent the rapid emergence of macrolide-resistant MAC. CONCLUSIONS: Treatment results for disseminated MAC infection remain poor. Therapy may be improved by selecting drugs on the basis of susceptibility data for each isolate, rather than by using empiric regimens based on susceptibility trends. Significant antimycobacterial drug malabsorption has been documented, and may contribute to poor outcomes. More-potent agents are needed to improve the clinical outcome in AIDS patients with MAC.

Animal and Cellular Models of Alzheimer’s Disease: Progress, Promise, and Future Approaches

2021 ◽  
pp. 107385842110017
Author(s):  
Laura Trujillo-Estrada ◽  
Elisabeth Sanchez-Mejias ◽  
Raquel Sanchez-Varo ◽  
Juan Antonio Garcia-Leon ◽  
Cristina Nuñez-Diaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Clinical Manifestations ◽  
Transgenic Mouse Models ◽  
In Vivo Models ◽  
Limited Ability ◽  
Cellular Models

Alzheimer’s disease (AD) is an incurable neurodegenerative disease affecting over 45 million people worldwide. Transgenic mouse models have made remarkable contributions toward clarifying the pathophysiological mechanisms behind the clinical manifestations of AD. However, the limited ability of these in vivo models to accurately replicate the biology of the human disease have precluded the translation of promising preclinical therapies to the clinic. In this review, we highlight several major pathogenic mechanisms of AD that were discovered using transgenic mouse models. Moreover, we discuss the shortcomings of current animal models and the need to develop reliable models for the sporadic form of the disease, which accounts for the majority of AD cases, as well as human cellular models to improve success in translating results into human treatments.

scholarly journals Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Athina Georgiadou ◽  
Claire Dunican ◽  
Pablo Soro-Barrio ◽  
Hyun Jae Lee ◽  
Myrsini Kaforou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Models ◽  
Mouse Models ◽  
Clinical Manifestations ◽  
Plasmodium Yoelii ◽  
Biological Mechanisms ◽  
Microvascular Pathology ◽  
High Parasite ◽  
Comparative Transcriptomic Analysis ◽  
Selection Of

Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.

Development of Transgenic Mouse Models for the Study of Human Olfactory Dysfunction

2005 ◽  
Vol 19 (3) ◽  
pp. 229-235 ◽  
Author(s):  
Andrew P. Lane ◽  
Haiqing Zhao ◽  
Randall R. Reed
Keyword(s):  
Animal Models ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Olfactory Dysfunction ◽  
Molecular Techniques ◽  
Model Systems ◽  
Olfactory Neuron ◽  
Transgenic Mouse Models ◽  
Olfactory Loss

Background Olfactory loss is a significant health problem that remains incompletely understood. The development of suitable animal models is essential to the progress of human olfactory loss research. Recent advancements in transgenic technology allow the creation of model systems to address causes of olfactory neuron dysfunction. Methods This review describes two transgenic mouse models with potential usefulness in the study of olfactory loss and highlights the molecular techniques that underlie the development of such systems. Results Genetic constructs generated using standard molecular biological techniques are introduced into mouse germ lines either by homologous recombination or by random integration. One construct (UbI7) places the olfactory receptor I7 under control of the olfactory marker protein promoter. The other two constructs (TI) act together to direct expression of cytokines in the olfactory epithelium, creating a novel approach to the study of inflammatory olfactory loss. Conclusions Powerful scientific tools now exist to develop animal models useful to the study of human olfactory disease. Transgenic olfactory neurons from the UbI7 mouse strain will respond to known odorants, facilitating experiments that examine in vitro modulation of olfactory neuron function. The ability to express specific genes in the olfactory mucosa of the TI mouse has great potential in elucidating the role of cytokines in the development of olfactory dysfunction in vivo.

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