The prion-like spreading of α-synuclein: From in vitro to in vivo models of Parkinson’s disease

Vargas, Jessica; Grudina, Clara; Zurzolo, Chiara

doi:10.1016/j.arr.2019.01.012

Cited by 72 publications

(69 citation statements)

References 137 publications

(261 reference statements)

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“…Previous studies have shown that α-syn can spread across brain regions [47][48][49]. Our study showed that hα-syn (A53T) expressed in SNc neurons can arrive at distant cerebral regions along projecting fibers.…”

Section: Neural Plasticitysupporting

confidence: 55%

Noncanonical Roles of hα-syn (A53T) in the Pathogenesis of Parkinson’s Disease: Synaptic Pathology and Neuronal Aging

et al. 2020

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The motor and nonmotor symptoms of PD involve several brain regions. However, whether α-syn pathology originating from the SNc can directly lead to the pathological changes in distant cerebral regions and induce PD-related symptoms remains unclear. Here, AAV9-synapsin-mCherry-human SNCA (A53T) was injected into the unilateral SNc of mice. Motor function and olfactory sensitivity were evaluated. Our results showed that AAV9-synapsin-mCherry-human SNCA was continuously expressed in SNc. The animals showed mild motor and olfactory dysfunction at 7 months after viral injection. The pathology in SNc was characterized by the loss of dopaminergic neurons accompanied by ER stress. In the striatum, hα-syn expression was high, CaMKβ-2 and NR2B expression decreased, and active synapses reduced. In the olfactory bulb, hα-syn expression was high, and aging cells in the mitral layer increased. The results suggested that hα-syn was transported in the striatum and OB along the nerve fibers that originated from the SNc and induced pathological changes in the distant cerebral regions, which contributed to the motor and nonmotor symptoms of PD.

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Section: Neural Plasticitysupporting

confidence: 55%

Noncanonical Roles of hα-syn (A53T) in the Pathogenesis of Parkinson’s Disease: Synaptic Pathology and Neuronal Aging

et al. 2020

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“…The extracellular secretion of key proteins implicated in neurodegenerative diseases, including α-synuclein, tau, and prion, via both exosomal and nonvesicular pathways has been reported [18,41,42,52]. Such secretion through dual pathways would accelerate their spread.…”

Section: Discussionmentioning

confidence: 99%

A novel function of FAF1, which induces dopaminergic neuronal death through cell-to-cell transmission

Park

Kim

2020

Cell Commun Signal

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Background: Fas-associated factor 1 (FAF1) has been implicated in Parkinson's disease (PD) and activates the cell death machinery in the cytosol. However, the presence of extracellular FAF1 has not been studied. Methods: Serum-free conditioned medium (CM) from FAF1-transfected SH-SY5Y cells was concentrated and analyzed by western blotting. Exosomes were isolated from CM by ultracentrifugation and analyzed by western blotting, electron microscopy and nanoparticle tracking analysis. Soluble FAF1 from CM was immunodepleted using anti-FAF1 antibody. Transmission of secreted FAF1 was examined by transwell assay under a confocal microscope. CM-induced cell death was determined by measuring propidium iodide (PI) uptake using a flow cytometer. Results: FAF1 was secreted from SH-SY5Y cells via exocytosis and brefeldin A (BFA)-resistant secretory pathways. Furthermore, FAF1 was secreted as a vesicle-free form and a genuine exosome cargo in the lumen of exosomes. In addition, FAF1 increased the number of exosomes, suggesting a regulatory role in exosome biogenesis. Extracellular FAF1 was transmitted via endocytosis to neighboring cells, where it induced cell death through apoptotic and necrotic pathways. Conclusions: This study presents a novel route by which FAF1 induces neuronal death through cell-to-cell transmission.

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“…4,5 This notwithstanding, both oligomers and fibrils have been found to induce neuronal cell death, [6][7][8] and can mediate the dissemination of α-syn pathology, although fibrils are considered the most prone to trigger the prion-like spreading. 6,[8][9][10][11] This evidence supports that as α-syn deposition plays a central role in the onset of several neurodegenerative disorders, reducing α-syn levels, oligomer formation, fibrillation, or cell-to-cell transmission, may all represent useful strategies to contrast/slow down the synucleinopathies, which still nowadays can only be managed by symptomatic therapies.…”

Section: Introductionmentioning

confidence: 60%

“…Since α‐syn is intrinsically disordered and does not own a defined tertiary structure in solution, while displaying different conformations depending on the surrounding environment (partially α‐helical and oligomeric species), it is also difficult to predict which are most relevant functional forms of the protein . This notwithstanding, both oligomers and fibrils have been found to induce neuronal cell death, and can mediate the dissemination of α‐syn pathology, although fibrils are considered the most prone to trigger the prion‐like spreading …”

Section: Introductionmentioning

confidence: 99%

The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

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The prion-like spreading of α-synuclein: From in vitro to in vivo models of Parkinson’s disease

Cited by 72 publications

References 137 publications

Noncanonical Roles of hα-syn (A53T) in the Pathogenesis of Parkinson’s Disease: Synaptic Pathology and Neuronal Aging

Noncanonical Roles of hα-syn (A53T) in the Pathogenesis of Parkinson’s Disease: Synaptic Pathology and Neuronal Aging

A novel function of FAF1, which induces dopaminergic neuronal death through cell-to-cell transmission

The good and bad of therapeutic strategies that directly target α‐synuclein

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