Caudo‐rostral brain spreading of α‐synuclein through vagal connections

Ulusoy, Ayşe; Rusconi, Raffaella; Pérez‐Revuelta, Blanca I.; Musgrove, Ruth E.; Helwig, Michael; Winzen‐Reichert, Bettina; Monte, Donato A. Di

doi:10.1002/emmm.201302475

Cited by 242 publications

(249 citation statements)

References 23 publications

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“…Similar phenomena are observed not only for monomeric α-synuclein, but also for oligomeric and fibrillar α-synuclein, the latter most likely being a significant contributor to the Lewy pathology propagation in PD conditions. The vagal route of α-synuclein transport has also been documented by systemic administration of the environmental toxin rotenone [36], as well as by directly injecting adeno-associated viral vectors overexpressing human α-synuclein into the vagal nerve [49]. The clear difference between the present study and previous work is that exogenous α-synuclein forms are not readily detected in the vagal nerves/neurons and the brain parenchyma [15,31,32,49].…”

Section: Discussionmentioning

confidence: 68%

Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

et al. 2014

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The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.

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Section: Discussionmentioning

confidence: 68%

Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

et al. 2014

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“…Numerous in vitro and in vivo studies showed that α-synuclein can be released from one cell, taken up by another, and seed aggregation of endogenous α-synuclein in the recipient cell, with resulting deleterious pathological changes [129,[241][242][243][244][245][246]. It is likely that this transmission can occur without cell death or membrane leakage of the donor cell, perhaps through exocytosis [247], although cell death and membrane degeneration would accelerate the transmission by releasing a large amount of α-synuclein aggregates.…”

Section: α-Synuclein "Strains" and Prion-like Transmissionmentioning

confidence: 92%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

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“…exposure to the environmental toxin rotenone (22) as well as following direct injection of adenoassociated viral vectors overexpressing human α-synuclein into the vagus nerve (23). A route from intrinsic enteric neurons to the vagus nerve is supported by the observation that both myenteric neurons and preganglionic vagal nerves express α-synuclein (24).…”

Section: Introductionmentioning

confidence: 99%