Defined α-synuclein prion-like molecular assemblies spreading in cell culture

Aulić, Suzana; Le, Tran Thanh Nhat; Moda, Fabio; Abounit, Saïda; Corvaglia, Stefania; Casalis, Loredana; Gustincich, Stefano; Zurzolo, Chiara; Tagliavini, Fabrizio; Legname, Giuseppe

doi:10.1186/1471-2202-15-69

Cited by 71 publications

(57 citation statements)

References 29 publications

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“…The damage induced by aSyn aggregates is also evident in synaptic terminals. However, the toxicity linked to exogenous aSyn is still not fully established, probably because it depends on the cellular type, on the endogenous levels of aSyn, or on the type and properties of the aSyn species used (38,49,(52)(53)(54). In the present study, two of four types of mature aSyn aggregates tested were significantly more toxic, strongly affecting neuronal structures.…”

Section: Discussionmentioning

confidence: 53%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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Section: Discussionmentioning

confidence: 53%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent experimental studies and observations in humans (e.g. grafted neurons in PD) have shown similarities in spreading, including cell-to-cell transmission, and self-perpetuation of other NDD-related proteins [7][8][9][10][11][12][13][14][15][16][17]. The observation of a prion-like internalization process of disease-associated ␣-synuclein in the human brain supported this notion [18].…”

Section: Introductionmentioning

confidence: 88%

Patterns of Tau and α-Synuclein Pathology in the Visual System

Rahimi

Milenković

Kovács

2015

JPD

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Abstract.Background: Spreading of misfolded proteins has been suggested for neurodegenerative diseases. The hierarchical distribution of protein deposits in Alzheimer's (AD) and Parkinson's disease (PD) supports this concept. Objectives: To evaluate ␣-synuclein and tau-deposition in the optic pathway as an excellent anatomical model, which follows a strict trajectory including a cortico-geniculate feedback connection. Methods: We immunostained the optic nerve, lateral geniculate nucleus (LGN), and occipital cortex for AT8 (phosphorylated tau), ␣-synuclein, and disease-associated prion protein (PrP) in 47 cases with tau pathology (AD type, argyrophilic grain disease, or progressive supranuclear palsy), 16 PD, and 5 Creutzfeldt-Jakob disease (CJD) cases, respectively. Results: We detected immunoreactivity for all proteins along the optic pathway. The optic nerve showed immunopositivity only in cases with tau (6/8, 75%) or ␣-synuclein (5/7, 71%) pathology. The LGN was involved also frequently (tau: 22/47, 46.8%; ␣-synuclein: 15/16, 93.7%; PrP 5/5, 100%). The occipital cortex was variably affected by tau or ␣-synuclein pathology, but always showed PrP immunoreactivity in the CJD cases. Tau pathology in the LGN correlated with tau immunoreactivity in the occipital cortex and Braak stages of neurofibrillary degeneration. In tauopathies, which do not involve the occipital cortex, like argyrophilic grain disease or progressive supranuclear palsy, tau pathology was more frequently astrocytic in the LGN. Conclusions: Our results have implications 1) for the understanding of disease spreading along neural pathways and 2) for the diagnostic evaluation of the visual system in neurodegenerative proteinopathies as a potential biomarker to evaluate disease progression or subgrouping of cases.

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“…Certain forms of α-syn located in the extracellular environment can be internalized and induce endogeneous α-syn to selfaggregate [6,18,[46][47][48][49]. This may represent a mechanism for the spread of aggregated α-syn in the PD brain.…”

Section: Intracellular Aggregation Propertiesmentioning

confidence: 99%

“…Short fragmented α-syn amyloid fibrils have also been reported to trigger endogenous α-syn to aggregate and accumulate sustainably over several passages in non-transfected and transfected SH-SY5Y cells [18]. The morphology and characteristics of intracellular inclusions have been demonstrated to be influenced by the variant of α-syn seed applied.…”

Section: Introductionmentioning

confidence: 99%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

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Defined α-synuclein prion-like molecular assemblies spreading in cell culture

Cited by 71 publications

References 29 publications

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Patterns of Tau and α-Synuclein Pathology in the Visual System

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

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