Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models

Autophagy ◽  
2022 ◽  
pp. 1-30
Author(s):  
Panagiota Mavroeidi ◽  
Fedra Arvanitaki ◽  
Maria Vetsi ◽  
Stefan Becker ◽  
Dimitrios Vlachakis ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein

Analysis of alpha-synuclein aggregation and associated pathologies in a cellular model of multiple system atrophy

2005 ◽  
Vol 32 (06) ◽  
Author(s):  
G Fillon ◽  
M Neumann ◽  
R Zufferey ◽  
P Aebischer ◽  
HA Kretzschmar ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein ◽  
Cellular Model ◽  
Alpha Synuclein Aggregation

scholarly journals Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

2021 ◽  
Author(s):  
Nelson Ferreira ◽  
Hjalte Gram ◽  
Zachary A. Sorrentino ◽  
Emil Gregersen ◽  
Sissel Ida Schmidt ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Resonance Energy Transfer ◽  
Lewy Bodies ◽  
Resonance Energy ◽  
Alpha Synuclein ◽  
Striatal Neurons ◽  
End Stage ◽  
Intracellular Aggregates

AbstractPathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.

The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy

2021 ◽  
pp. 1-11
Author(s):  
David I. Finkelstein ◽  
Jay J. Shukla ◽  
Robert A. Cherny ◽  
Jessica L. Billings ◽  
Eiman Saleh ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Pharmacokinetic Profile ◽  
Alpha Synuclein ◽  
Redox Activity ◽  
Substantia Nigra Pars Compacta ◽  
Drug Candidate ◽  
Older Volunteers ◽  
Control Food ◽  
Alpha Synuclein Aggregation

Background: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective: To evaluate the efficacy of ATH434 in a mouse MSA model. Methods: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric species of synuclein. Conclusion: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.

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 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.

Analysis of colonic alpha-synuclein pathology in multiple system atrophy

2012 ◽  
Vol 18 (7) ◽  
pp. 893-895 ◽  
Author(s):  
Hélène Pouclet ◽  
Thibaud Lebouvier ◽  
Emmanuel Coron ◽  
Tiphaine Rouaud ◽  
Mathurin Flamant ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein

scholarly journals Correction to: Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models

2019 ◽  
Vol 138 (4) ◽  
pp. 675-675
Author(s):  
Panagiota Mavroeidi ◽  
Fedra Arvanitaki ◽  
Anastasia-Kiriaki Karakitsou ◽  
Maria Vetsi ◽  
Ismini Kloukina ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein

scholarly journals Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson's Disease and Multiple System Atrophy

2021 ◽  
Author(s):  
Rahul Pande ◽  
Yinyin Huang ◽  
Erin Teeple ◽  
Pooja Joshi ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Single Cell ◽  
Alpha Synuclein ◽  
Cell Type ◽  
Distinct Cell Type ◽  
Altered Expression ◽  
Cell Type Specific ◽  
Disease Specific

Understanding disease biology at a cellular level from disease specific tissues is imperative for effective drug development for complex neurodegenerative diseases. We profiled 87,086 nuclei from putamen tissue of healthy controls, Parkinson's Disease (PD), and Multiple System Atrophy (MSA) subjects to construct a comprehensive single cell atlas. Although both PD and MSA are manifestations of alpha-synuclein protein aggregation, we observed that both the diseases have distinct cell-type specific changes. We see a possible expansion and activation of microglia and astrocytes in PD compared to MSA and controls. Contrary to PD microglia, we found absence of upregulated unfolded protein response in MSA microglia compared to controls. Differentially expressed genes in major cell types are enriched for genes associated with PD-GWAS loci. We found altered expression of major neurodegeneration associated genes, SNCA, MAPT, LRRK2, and APP, at cell-type resolution. We also identified disease associated gene modules using a network biology approach. Overall, this study creates an interactive atlas from synucleinopathies and provides major cell-type specific disease insights.

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