Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

Tyson, Trevor; Steiner, Jennifer A.; Brundin, Patrik

doi:10.1111/jnc.13449

Cited by 82 publications

(69 citation statements)

References 188 publications

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“…; Tyson et al . ). Increased secretion of α‐synuclein with FYCO1 over‐expression is supported by the extracellular electron‐dense material observed with electron microscopy (Fig.…”

Section: Discussionmentioning

confidence: 97%

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Saridaki

Nippold

Dinter

et al. 2018

Journal of Neurochemistry

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Parkinson's disease can be caused by mutations in the α-synuclein gene and is characterized by aggregates of α-synuclein protein. We have previously shown that over-expression of the small GTPase Rab7 can induce clearance of α-synuclein aggregates. In this study, we investigate which Rab7 effectors mediate this effect. To model Parkinson's disease, we expressed the pathogenic A53T mutant of α-synuclein in HEK293T cells and Drosophila melanogaster. We tested the Rab7 effectors FYVE and coiled-coil domain-containing protein 1 (FYCO1) and Rab-interacting lysosomal protein (RILP). FYCO1-EGFP-decorated vesicles containing α-synuclein. RILP-EGFP also decorated vesicular structures, but they did not contain α-synuclein. FYCO1 over-expression reduced the number of cells with α-synuclein aggregates, defined as visible particles of EGFP-tagged α-synuclein, whereas RILP did not. FYCO1 but not RILP reduced the amount of α-synuclein protein as assayed by western blot, increased the disappearance of α-synuclein aggregates in time-lapse microscopy and decreased α-synuclein-induced toxicity assayed by the Trypan blue assay. siRNA-mediated knockdown of FYCO1 but not RILP reduced Rab7-induced aggregate clearance. Collectively, these findings indicate that FYCO1 and not RILP mediates Rab7-induced aggregate clearance. The effect of FYCO1 on aggregate clearance was blocked by dominant negative Rab7 indicating that FYCO1 requires active Rab7 to function. Electron microscopic analysis and insertion of lysosomal membranes into the plasma membrane indicate that FYCO1 could lead to secretion of α-synuclein aggregates. Extracellular α-synuclein as assayed by ELISA was, however, not increased with FYCO1. Coexpression of FYCO1 in the fly model decreased α-synuclein aggregates as shown by the filter trap assay and rescued the locomotor deficit resulting from neuronal A53T-α-synuclein expression. This latter finding confirms that a pathway involving Rab7 and FYCO1 stimulates degradation of α-synuclein and could be beneficial in patients with Parkinson's disease. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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“…; Tyson et al . ). Increased secretion of α‐synuclein with FYCO1 over‐expression is supported by the extracellular electron‐dense material observed with electron microscopy (Fig.…”

Section: Discussionmentioning

confidence: 97%

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Saridaki

Nippold

Dinter

et al. 2018

Journal of Neurochemistry

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“…Furthermore, there is growing evidence that α-synuclein may act in a prion-like manner such that misfolded α-synuclein can be propagated from cell to cell [35, 118, 164, 370], even in wild-type non-transgenic mice [229]. The relationship between AD pathology and α-synuclein is unclear, although studies suggest that α-synuclein can act synergistically with both tau [105] and Aβ [234] to promote their aggregation and accumulation.…”

Section: α-Synuclein Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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“…Recent reviews describe these areas in detail (3,63,64) and we only provide a short overview. It is important to emphasize that underlying mechanisms differ depending on whether the α-synuclein is present as a monomer, oligomer or fibril.…”

Section: Cellular and Molecular Mechanisms Of α-Synuclein Intercellulmentioning

confidence: 99%

How strong is the evidence that Parkinson's disease is a prion disorder?

Brundin¹,

Ma²,

Kordower

2016

Current Opinion in Neurology

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Purpose of review We describe evidence supporting the hypothesis that α-synuclein has a prion-like role in Parkinson’s disease and related α-synucleinopathies, and discuss how this novel thinking impacts the development of diagnostics and disease-modifying therapies. Recent findings Observations that immature dopamine neurons grafted to Parkinson’s disease patients can develop Lewy bodies triggered a surge of interest in the putative prion-like properties of α-synuclein. We recount results from experiments which confirm that misfolded α-synuclein can exhibit disease-propagating properties, and describe how they relate to the spreading of α-synuclein aggregates in α-synucleinopathies. We share insights into the underlying molecular mechanisms and their relevance to novel therapeutic targets. Finally, we discuss what the initial triggers of α-synuclein misfolding might be, where in the body the misfolding events might take place and how this can instruct development of novel diagnostic tools. We speculate that differences in anatomical trigger sites and variability in α-synuclein fibril structure can contribute to clinical differences between α-synucleinopathies. Summary The realization that α-synuclein pathology can propagate between brain regions in neurodegenerative diseases has deepened and expanded our understanding of potential pathogenic processes which can lead to the development of novel diagnostic tools as well as the identification of new therapeutic targets.

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Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

Cited by 82 publications

References 188 publications

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism

Current state of Alzheimer’s fluid biomarkers

How strong is the evidence that Parkinson's disease is a prion disorder?

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