The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

Jan, Asad; Gonçalves, Nádia Pereira; Vægter, Christian Bjerggaard; Jensen, Poul Henning; Ferreira, Nelson

doi:10.3390/ijms22158338

Cited by 67 publications

(52 citation statements)

References 261 publications

(384 reference statements)

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“…The appearance of multiple distinct conformation α-syn fibrils under identical conditions may also be one of the steps in the complex mechanism of pathogenesis in Parkinson's disease and other synucleinopathies. Currently, the exact mode of alpha-synuclein-related disorder onset and propagation is not fully known, with multiple possible mechanisms proposed, such as prion-like spreading [38] and trans-synaptic α-syn propagation [39,40]. It has also recently been shown by Ferreira et al [41] and Peng et al [42] that certain α-syn fibril types have a considerably higher neurodegenerative potential than others.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration

Žiaunys

Sakalauskas

Mikalauskaite

et al. 2021

IJMS

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Protein aggregate formation is linked with multiple amyloidoses, including Alzheimer‘s and Parkinson‘s diseases. Currently, the understanding of such fibrillar structure formation and propagation is still not sufficient, the outcome of which is a lack of potent, anti-amyloid drugs. The environmental conditions used during in vitro protein aggregation assays play an important role in determining both the aggregation kinetic parameters, as well as resulting fibril structure. In the case of alpha-synuclein, ionic strength has been shown as a crucial factor in its amyloid aggregation. In this work, we examine a large sample size of alpha-synuclein aggregation reactions under thirty different ionic strength and protein concentration combinations and determine the resulting fibril structural variations using their dye-binding properties, secondary structure and morphology. We show that both ionic strength and protein concentration determine the structural variability of alpha-synuclein amyloid fibrils and that sometimes even identical conditions can result in up to four distinct types of aggregates.

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Section: Discussionmentioning

confidence: 99%

Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration

Žiaunys

Sakalauskas

Mikalauskaite

et al. 2021

IJMS

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“…The self-aggregation of α-syn promotes membrane disruption, which can result from the formation of an amphipathic helical structure of α-syn [ 6 ]. Modern views of PD encompass the cell-to-cell trans-synaptic spread of α-syn [ 25 , 26 ] and the existence of many α-syn polymorphs that might be responsible for different synucleinopathies [ 27 , 28 ]. The cell membrane containing integrins is thought to play an important role in the intercellular synaptic diffusion of α-syn.…”

Section: Discussionmentioning

confidence: 99%

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

Han

Seo

Lim

2021

IJMS

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We investigated the potential association between integrin α7 (ITGA7) and alpha-synuclein (α-syn) in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. Tyrosine hydroxylase (TH), ITGA7, and α-syn expression in the substantia nigra (SN) of the brain were observed to examine the pathological characteristics of PD. To determine the relationship between ITGA7 and PD, the expression of TH and α-syn was investigated after ITGA7 siRNA knockdown in SH-SY5Y cells. The ITGA7 microarray signal was decreased in the SN of the MPTP group, indicating reduced ITGA7 expression compared to that in the control. The expression patterns of ITGA7 in the control group and those of α-syn in the MPTP group were similar on immunohistochemical staining. Reduction in ITGA7 expression by ITGA7 siRNA administration induced a decrease in TH expression and an increase in α-syn expression in SH-SY5Y cells. The decreased expression of ITGA7 significantly decreased the expression of bcl2 and increased the bax/bcl2 ratio in SH-SY5Y cells. These results suggest that reduced ITGA7 expression may be related to increased α-syn expression and apoptosis of dopaminergic cells in an MPTP-induced PD mouse model. To the best of our knowledge, this is the first study to show an association between ITGA7 and PD.

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“…Intraneuronal αSyn aggregates are triggered by internalized small fibers that do not contact membranes directly, suggesting that this mechanism is relevant to the spreading of aggregated pathologies [76]. Although the molecular mechanisms responsible for spreading pathologic αSyn are poorly understood, a growing body of evidence indicates that de novo misfolding and/or neuronal internalization of aggregated αSyn facilitates conformational templating of endogenous αSyn monomers in a prion-like manner [77]. Recent studies demonstrating that cellular prion protein (PrP C ) mediates αSyn uptake, localization, and toxicity in vitro and in vivo confirmed previous results which showed that PrP C internalizes soluble misfolded αSyn, indicating its important role in its internalization required for the intercellular spread of αSyn [78].…”

Section: Self-propagation Of Prionoidsmentioning

confidence: 99%

Is Multiple System Atrophy a Prion-like Disorder?

Jellinger¹,

Wenning

Stefanova

2021

IJMS

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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.

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The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

Cited by 67 publications

References 261 publications

Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration

Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

Is Multiple System Atrophy a Prion-like Disorder?

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