Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays

Candelise, Niccolò; Schmitz, Matthias; Thüne, Katrin; Cramm, Maria; Rábano, Alberto; Zafar, Saima; Stoops, Erik; Vanderstichele, Hugo; Villar‐Piqué, Anna; Llorens, Franc; Zerr, Inga

doi:10.1186/s40035-019-0181-9

Cited by 62 publications

(50 citation statements)

References 130 publications

(150 reference statements)

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“…The use of recombinant aSyn monomers purified from E. coli (Huang et al, 2005) enables studying and inducing aSyn fibril formation in a very controlled and clean environment. For this, different protocols can be applied, however, many involve constant agitation (120-1,000 rpm) for different timeframes in different buffer systems (Narkiewicz et al, 2014;Candelise et al, 2020). It was also described, that the addition of a single glass or PTFE (poly tera-flour-ethylene) bead enhances the formation of aSyn fibrils (Buell et al, 2014;Narkiewicz et al, 2014).…”

Section: Structural Aspects Of Asyn Pathologymentioning

confidence: 99%

“…Interestingly, a different fibrillary architecture was found for MSA patients, where the cellular source of aggregated aSyn is not neuronal, but stems from oligodendrocytes ( Shahnawaz et al, 2020 ). Hence, the cellular environment seems to influence the aggregation pattern and fibrillary structure of aSyn significantly ( Candelise et al, 2020 ). Thus, high-resolution structural comparison of GIT- and CNS-derived aSyn conformers could help to better understand the role of the gut-brain axis in PD.…”

Section: Structural Aspects Of Asyn Pathologymentioning

confidence: 99%

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Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

Schaeffer

Kluge

Böttner

et al. 2020

Front. Cell Dev. Biol.

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Parkinson's disease (PD) is marked by different kinds of pathological features, one hallmark is the aggregation of α-synuclein (aSyn). The development of aSyn pathology in the substantia nigra is associated to the manifestation of motor deficits at the time of diagnosis. However, most of the patients suffer additionally from non-motor symptoms, which may occur already in the prodromal phase of the disease years before PD is diagnosed. Many of these symptoms manifest in the gastrointestinal system (GIT) and some data suggest a potential link to the occurrence of pathological aSyn forms within the GIT. These clinical and pathological findings lead to the idea of a gut-brain route of aSyn pathology in PD. The identification of pathological aSyn in the intestinal system, e.g., by GIT biopsies, is therefore of highest interest for early diagnosis and early intervention in the phase of formation and propagation of aSyn. However, reliable methods to discriminate between physiological and pathological forms of enteral aSyn on the cellular and biochemical level are still missing. Moreover, a better understanding of the physiological function of aSyn within the GIT as well as its structure and pathological aggregation pathways are crucial to understand its role within the enteric nervous system and its spreading from the gut to the brain. In this review, we summarize clinical manifestations of PD in the GIT, and discuss biochemical findings from enteral biopsies. The relevance of pathological aSyn forms, their connection to the gut-brain axis and new developments to identify pathologic forms of aSyn by structural features are critically reviewed.

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Section: Structural Aspects Of Asyn Pathologymentioning

confidence: 99%

Section: Structural Aspects Of Asyn Pathologymentioning

confidence: 99%

Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

Schaeffer

Kluge

Böttner

et al. 2020

Front. Cell Dev. Biol.

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“…In particular, MSA and PD strains seem to have different structural and seed properties that may be used as differential diagnostic criteria and that could explain the more aggressive and rapid progression of MSA compared to other synucleinopathies (Peng et al, 2018b ; Candelise et al, 2019 ; Yamasaki et al, 2019 ; Schweighauser et al, 2020 ; Shahnawaz et al, 2020 ; Van Der Perren et al, 2020 ). It is not yet clear how the different α-syn strains are generated, but the cellular micro-environment may play an important role (Candelise et al, 2020 ). Thus, a recent publication by the group of Virginia Lee showed that the α-syn extracted from GCIs presents a different proteolytic profile and more potent biological activity than the α-syn from LBs and that the specific cellular milieu of oligodendrocytes is responsible for the transformation of misfolded α-syn into the MSA strain (Peng et al, 2018a ).…”

Section: Aggregation and Spreading Of α-Synmentioning

confidence: 99%

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

Heras‐Garvin

Stefanova

2020

Front. Synaptic Neurosci.

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Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.

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“…However, very few studies have focused on the effects of intracellular alpha-synuclein (and its pathologic forms) on immune cells. Several observations suggest that such effects may take place and be relevant for disease: (i) some studies have shown that the local environment may be at least partly responsible for alpha-synuclein pathology, which can therefore take place also in immune cells ( Candelise et al, 2020 ) (ii) genetic aberrations such as point mutations, duplications, and triplications are systemic and found also in immune cells ( Gardai et al, 2013 ; Haenseler et al, 2017 ) (iii) alpha-synuclein is capable of escaping into the intracellular space after uptake by cells ( Freeman et al, 2013 ; Flavin et al, 2017 ). The detailed study of the effects of intracellular alpha-synuclein on immune cells bears potential in two main aspects: It may reveal so-far-overseen mechanisms of neuroinflammation, and can hold diagnostic value, as peripheral immune cells are easily accessible.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Alpha-Synuclein and Immune Cell Function

Grozdanov

Danzer

2020

Front. Cell Dev. Biol.

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Intracellular alpha-synuclein has numerous effects on different functions of the cell. Although it is expressed in a wide spectrum of cell types from different lineages, most of our knowledge about it was generated by studying neuronal or glial cells. However, the role of immune cells in Parkinson's disease and related synucleinopathies has recently emerged. Altered immune cell phenotypes and functions have been reported not only in animal models, but also in human disease. While the response of immune cells to extracellular alpha-synuclein has been thoroughly studied, insights into the effects of endogenously expressed or taken-up alpha-synuclein on the function of immune cells remain scarce. Such insights may prove to be important for understanding the complex cellular and molecular events resulting in neurodegeneration and aid the development of novel therapies. We review the current state of knowledge about how alpha-synuclein and its pathologic manifestations affect the phenotype and function of peripheral and central nervous system (CNS) immune cells, and discuss the potential of this topic for advancing our understanding of synucleinopathies.

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Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays

Cited by 62 publications

References 130 publications

Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

Intracellular Alpha-Synuclein and Immune Cell Function

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