2022
DOI: 10.1007/s00401-022-02406-7
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Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations

Abstract: The protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-syn… Show more

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Cited by 17 publications
(11 citation statements)
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“…[104,105] Our data showing differential intrinsic and extrinsic responses of VMB-and STR-AS fit with the reported high level of AS heterogeneity in the CNS, whose regulatory mechanisms (e.g., transcriptional versus epigenetic programs) remain as outstanding open questions for the field. [77,129,133,134] Indeed, the molecular machinery which orchestrates the distinct EV secretion ratesaccording to the brain region and the specific exposure to inflammatory triggers-needs to be further elucidated. Also, these findings call for a deeper understanding of the functional implications of such a specific response to microenvironmental cues between VMB (where the DAergic neurons reside) versus STR (where they project) for the pathogenesis of PD and, eventually, for the development of new therapeutic avenues.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…[104,105] Our data showing differential intrinsic and extrinsic responses of VMB-and STR-AS fit with the reported high level of AS heterogeneity in the CNS, whose regulatory mechanisms (e.g., transcriptional versus epigenetic programs) remain as outstanding open questions for the field. [77,129,133,134] Indeed, the molecular machinery which orchestrates the distinct EV secretion ratesaccording to the brain region and the specific exposure to inflammatory triggers-needs to be further elucidated. Also, these findings call for a deeper understanding of the functional implications of such a specific response to microenvironmental cues between VMB (where the DAergic neurons reside) versus STR (where they project) for the pathogenesis of PD and, eventually, for the development of new therapeutic avenues.…”
Section: Discussionmentioning
confidence: 99%
“…[40][41][42][44][45][46][47][48][49][50]73,89,94,127,128] Especially, the heterogeneous nature of AS has been emphasized, showing regional AS differential responses to both genetic and environmental factors, including ageing, inflammatory or neurotoxin exposures, all crucial conditions of vulnerability for PD. [40,41,44,45,73,81,88,129] Yet, the modality of the intricate AS-neuron crosstalk still remains undefined. Among the multiple modes of intercellular communication, the secretion of EVs has emerged as a powerful tool for the exchange of information.…”
Section: Discussionmentioning
confidence: 99%
“…Imaging studies have also suggested two distinct temporal models of αSyn pathology progression [ 13 ]. Recent reports have indicated that there may be more structural heterogeneity of the αSyn protein in different synucleinopathies than previously understood [ 7 , 35 , 50 ] and it remains to be investigated whether this heterogeneity is linked to distinct temporal patterns of αSyn pathology progression.…”
Section: Discussionmentioning
confidence: 99%
“…Highly enriched in presynaptic terminals, α-synuclein regulates vesicle fusion and neurotransmitter release in normal physiology [ 187 ]. Current research indicates that physiological α-synuclein is subject to dynamic equilibrium between an unstructured monomer and an α-helical multimer [ 188 , 189 , 190 ], with multimerization implicated in binding the synaptic vesicle membrane. Misfolded α-synuclein oligomers accumulate in neuropathology, causing progressive synaptic dysfunction, membrane permeabilization, prion-like cell-to-cell spreading, and eventual neuronal death.…”
Section: Impact Of O-glcnac In Physiological Models Of Injury and Pat...mentioning
confidence: 99%