scholarly journals Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lisa Mészáros ◽  
Markus J. Riemenschneider ◽  
Heiko Gassner ◽  
Franz Marxreiter ◽  
Stephan von Hörsten ◽  
...  
Keyword(s):  
Mouse Model ◽  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Purkinje Cells ◽  
Alpha Synuclein ◽  
Significant Loss ◽  
Disease Stage ◽  
Cytoplasmic Inclusions ◽  
Unsteady Gait ◽  
Advanced Disease Stage

AbstractMultiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

scholarly journals Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

2020 ◽  
Vol 21 (8) ◽  
pp. 2775 ◽  
Author(s):  
Lisa Mészáros ◽  
Alana Hoffmann ◽  
Jeanette Wihan ◽  
Jürgen Winkler
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Autonomic Failure ◽  
Neuronal Loss ◽  
Symptomatic Treatment ◽  
Alpha Synuclein ◽  
Rapid Progression ◽  
Cytoplasmic Inclusions ◽  
Atypical Parkinsonian Syndrome ◽  
Disease Modifying

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

scholarly journals Multiple system atrophy: genetic risks and alpha-synuclein mutations

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2072 ◽  
Author(s):  
Heather T Whittaker ◽  
Yichen Qui ◽  
Conceição Bettencourt ◽  
Henry Houlden
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Research Collaboration ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Common Mechanism ◽  
International Research Collaboration ◽  
Cytoplasmic Inclusions ◽  
Genetic Risks

Multiple system atrophy (MSA) is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings. Families with certain types of α-synuclein mutations develop diseases that mimic MSA, and the spectrum of clinical and pathological features in these families suggests a spectrum of severity, from late-onset Parkinson’s disease to MSA. Nonetheless, controversies persist, such as the role of common α-synuclein variants in MSA and whether this disorder shares a common mechanism of spreading pathology with other protein misfolding neurodegenerative diseases. Here, we review these issues, specifically focusing on α-synuclein mutations.

scholarly journals A historical review of multiple system atrophy with a critical appraisal of cellular and animal models

2021 ◽  
Author(s):  
David J. Marmion ◽  
Wouter Peelaerts ◽  
Jeffrey H. Kordower
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Rem Sleep Behavior Disorder ◽  
Alpha Synuclein ◽  
Motor Symptom ◽  
Olivopontocerebellar Atrophy ◽  
Prodromal Phase ◽  
Sleep Behavior ◽  
Cytoplasmic Inclusions

AbstractMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.

scholarly journals Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

2022 ◽  
Author(s):  
Berkiye Sonustun ◽  
Firat M Altay ◽  
Catherine Strand ◽  
Geshanthi Hondhamuni ◽  
Thomas T Warner ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Post Translational Modifications ◽  
Variable Extent ◽  
Neurologically Normal ◽  
Main Component ◽  
Initiating Factors

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

scholarly journals Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy

Glia ◽  
2013 ◽  
Vol 62 (2) ◽  
pp. 317-337 ◽  
Author(s):  
Elvira Valera ◽  
Kiren Ubhi ◽  
Michael Mante ◽  
Edward Rockenstein ◽  
Eliezer Masliah
Keyword(s):  
Mouse Model ◽  
Multiple System Atrophy ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Alpha Synuclein

Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia

2010 ◽  
Vol 40 (2) ◽  
pp. 415-423 ◽  
Author(s):  
Jonathan Jones ◽  
Jesús Jaramillo-Merchán ◽  
Carlos Bueno ◽  
Diego Pastor ◽  
MariCarmen Viso-León ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Cerebellar Ataxia ◽  
Purkinje Cells ◽  
Motor Functions

scholarly journals In vivo 5-ethynyluridine (EU) labelling detects reduced transcription in Purkinje cell degeneration mouse mutants, but can itself induce neurodegeneration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lisanne J. van’t Sant ◽  
Joshua J. White ◽  
Jan H. J. Hoeijmakers ◽  
Wilbert P. Vermeij ◽  
Dick Jaarsma
Keyword(s):  
Nervous System ◽  
Mouse Model ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Cell Degeneration ◽  
Cytoplasmic Inclusions ◽  
Purkinje Cell Degeneration ◽  
System Disease ◽  
Mouse Mutants

AbstractFluorescent staining of newly transcribed RNA via metabolic labelling with 5-ethynyluridine (EU) and click chemistry enables visualisation of changes in transcription, such as in conditions of cellular stress. Here, we tested whether EU labelling can be used to examine transcription in vivo in mouse models of nervous system disorders. We show that injection of EU directly into the cerebellum results in reproducible labelling of newly transcribed RNA in cerebellar neurons and glia, with cell type-specific differences in relative labelling intensities, such as Purkinje cells exhibiting the highest levels. We also observed EU-labelling accumulating into cytoplasmic inclusions, indicating that EU, like other modified uridines, may introduce non-physiological properties in labelled RNAs. Additionally, we found that EU induces Purkinje cell degeneration nine days after EU injection, suggesting that EU incorporation not only results in abnormal RNA transcripts, but also eventually becomes neurotoxic in highly transcriptionally-active neurons. However, short post-injection intervals of EU labelling in both a Purkinje cell-specific DNA repair-deficient mouse model and a mouse model of spinocerebellar ataxia 1 revealed reduced transcription in Purkinje cells compared to controls. We combined EU labelling with immunohistology to correlate altered EU staining with pathological markers, such as genotoxic signalling factors. These data indicate that the EU-labelling method provided here can be used to identify changes in transcription in vivo in nervous system disease models.

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