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Brain-to-stomach transfer of ?-synuclein via vagal preganglionic projections.

ABSTRACT: Detection of ?-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between ?-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of ?-synuclein from the rat brain to the stomach. Following targeted midbrain overexpression of human ?-synuclein, the exogenous protein was capable of reaching the gastric wall where it was accumulated into preganglionic vagal terminals. This brain-to-stomach connection likely involved intra- and inter-neuronal transfer of non-fibrillar ?-synuclein that first reached the medulla oblongata, then gained access into cholinergic neurons of the dorsal motor nucleus of the vagus nerve and finally traveled via efferent fibers of these neurons contained within the vagus nerve. Data also showed a particular propensity of vagal motor neurons and efferents to accrue ?-synuclein and deliver it to peripheral tissues; indeed, following its midbrain overexpression, human ?-synuclein was detected within gastric nerve endings of visceromotor but not viscerosensory vagal projections. Thus, the dorsal motor nucleus of the vagus nerve represents a key relay center for central-to-peripheral ?-synuclein transmission, and efferent vagal fibers may act as unique conduits for protein transfer. The presence of ?-synuclein in peripheral tissues could reflect, at least in some synucleinopathy patients, an ongoing pathological process that originates within the brain and, from there, reaches distant organs innervated by motor vagal projections.

SUBMITTER: Ulusoy A

PROVIDER: S-EPMC5326583 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections.

Ulusoy Ayse A Phillips Robert J RJ Helwig Michael M Klinkenberg Michael M Powley Terry L TL Di Monte Donato A DA

Acta neuropathologica 20161223 3

Detection of α-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between α-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of α-synuclein from the rat brain to the stomach ...[more]

PMID: 28012041

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Project description:Cerebral deposition of abnormally aggregated α-synuclein (αSyn) is a neuropathological hallmark of Parkinson's disease (PD). PD-associated αSyn (αSynPD) aggregates can act as proteinaceous nuclei ("seeds") able of self-templated propagation. Since this is strikingly reminiscent to properties of proteinaceous infectious particles (prions), lessons learned from prion diseases suggest to test whether transferred αSynPD can propagate and induce neurological impairments or disease in a new host. Two studies that addressed this question provided divergent results. Intracerebral (i.c.) injection of Lewy body extracts from PD patients caused cerebral αSyn pathology, as well as nigrostriatal neurodegeneration, of wild-type mice and macaques, with the mice also showing motor impairments (Recasens et al. 2014, Ann Neurol 75:351-362). In contrast, i.c. transmission of homogenates from PD brains did not stimulate, after "> 360" days post-injection (dpi), pathological αSyn conversion or clinical symptoms in transgenic TgM83+/- mice hemizygously expressing mutated (A53T) human αSyn (Prusiner et al. 2015, PNAS 112:E5308-E5317). To advance the assessment of possible αSynPD hazards by providing further data, we examined neuropathological and clinical effects upon i.c. transmission of brain, stomach wall and muscle tissue as well as blood from PD patients in TgM83+/- mice up to 612 dpi. This revealed a subtle, yet distinctive stimulation of localized αSyn aggregation in the somatodendritic compartment and dystrophic neurites of individual or focally clustered cerebral neurons after challenge with brain and stomach wall homogenates. No such effect was observed with transmitted blood or homogenized muscle tissue. The detected stimulation of αSyn aggregation was not accompanied by apparent motor impairments or overt neurological disease in TgM83+/- mice. Our study substantiated that transmitted αSynPD seeds, including those from the stomach wall, are able to propagate in new mammalian hosts. The consequences of such propagation and potential safeguards need to be further investigated.

Dataset Information

Brain-to-stomach transfer of ?-synuclein via vagal preganglionic projections.

Publications

Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections.

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