Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 21, 2021

α-Synuclein is critical in the pathogenesis of Parkinson's disease and related disorders, yet it remains unclear how its aggregation causes degeneration human dopaminergic neurons. In this study, we induced α-synuclein iPSC-derived neurons using fibrils generated de novo or amplified presence brain homogenates from multiple system atrophy. Increased monomer levels promote seeded a dose time-dependent manner, which associated with further increase gene expression. Progressive neuronal death observed brain-amplified reversed by reduction intraneuronal abundance. We identified 56 proteins differentially interacting aggregates triggered fibrils, including evasion disease-associated deglycase DJ-1. Knockout DJ-1 enhance fibril-induced death. Taken together, our results show that toxicity strains depends on aggregate burden, determined conformation dictates differential interactomes. Our study demonstrates genes influence phenotypic manifestation

Language: Английский

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The 3D structure of lipidic fibrils of α-synuclein

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 10, 2022

α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which are characteristic hallmark neuronal inclusions called Lewy bodies. Studies on the composition bodies extracted postmortem from brain tissue patients revealed that lipids membranous organelles also significant component. Interactions between have been previously identified relevant for disease pathology, however molecular insights their interactions remained elusive. Here we present cryo-electron microscopy structures six complex with lipids, revealing specific lipid-fibril interactions. We observe phospholipids promote an alternative protofilament fold, mediate unusual arrangement protofilaments, fill central cavities fibrils. Together our previous studies, these indicate mechanism fibril-induced lipid extraction, likely to be involved development α-synucleinopathies. Specifically, one potential cellular toxicity disruption intracellular vesicles mediated by oligomers, therefore modulation may provide promising strategy future therapeutic interventions.

Language: Английский

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Molecular chaperones and Parkinson's disease

Neurobiology of Disease, Journal Year: 2021, Volume and Issue: 160, P. 105527 - 105527

Published: Oct. 8, 2021

Parkinson's disease (PD) is a neurodegenerative characterized by progressive death of dopaminergic neurons in the substantia nigra and formation Lewy bodies (LBs). Mutations PD-related genes lead to neuronal pathogenesis through various mechanisms, with known examples including SNCA/α-synuclein (PAKR1), Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), LRRK2 (PARK8). Molecular chaperones/co-chaperones are proteins that aid folding other into functionally active conformation. It has been demonstrated interact regulate their function PD. HSP70, HSP90 small heat shock can prevent neurodegeneration regulating α-syn misfolding, oligomerization aggregation. The chaperones regulated co-chaperones such as HSP110, HSP40, HOP, CHIP, BAG family proteins. Parkin, which associated mitochondrial function. protein homeostasis interacting these This review discusses critical molecular contribute PD, hoping provide new targets for therapeutic interventions thwart progression instead only bringing symptomatic relief. Moreover, appreciating role PD also help us screen efficient biomarkers identify at an early stage.

Language: Английский

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Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(10)

Published: Sept. 17, 2021

Dopaminergic (DA) cell death in Parkinson's disease (PD) is associated with the gradual appearance of neuronal protein aggregates termed Lewy bodies (LBs) that are comprised vesicular membrane structures and dysmorphic organelles conjunction alpha-Synuclein (α-Syn). Although exact mechanism aggregate formation remains elusive, recent research suggests α-Syn-mediated alterations lysosomal degradation aggregated proteins - a process autophagy. Here, we used combination molecular biology immunochemistry to investigate effect α-Syn on autophagy turnover cultured human DA neurons post-mortem brain tissue. We found overexpression reduce by compromising fusion autophagosomes lysosomes, thus leading decrease autolysosomes. In accord compensatory increase plasma autophagosomes, enhanced number extracellular vesicles (EV) abundance autophagy-associated these EVs. Mechanistically, decreased v-SNARE SNAP29, member SNARE complex mediating autophagolysosome fusion. line, SNAP29 knockdown mimicked whereas co-expression reversed α-Syn-induced changes EV release ameliorated death. our results from neurons, stage-dependent reduction SNc tissue body pathology (LBP) cases. summary, demonstrate previously unknown intracellular and, as consequence, reduced autolysosome As such, findings will therefore support investigation pathological PD.

Language: Английский

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Monitoring α-synuclein aggregation

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 176, P. 105966 - 105966

Published: Dec. 15, 2022

Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding subsequent aggregation of alpha-synuclein (α-syn) that accumulates in cytoplasmic inclusions bodies cells affected brain regions. Since seminal report likely-aggregated α-syn presence within Spillantini et al. 1997, keyword "synuclein aggregation" has appeared over 6000 papers (Source: PubMed October 2022). Studying, observing, describing, quantifying is therefore paramount importance, whether it happens tubo, vitro, post-mortem samples, or vivo. The past few years have witnessed tremendous progress understanding mechanisms identifying various polymorphs. In this context growing complexity, utmost importance to understand what tools we possess, exact information they provide, may be applied. Nonetheless, also crucial rationalize relevance limitations these methods for gauging final result. review, present main techniques shaped current views about structure dynamics, particular emphasis on recent breakthroughs change our synucleinopathies.

Language: Английский

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