Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology

Raiss, C.C.; Braun, Theresa; Konings, Irene B.M.; Grabmayr, Heinrich; Hassink, Gerco; Sidhu, Arshdeep; Feber, Joost le; Bausch, Andreas R.; Jansen, Casper; Subramaniam, Vinod; Claessens, Mireille Maria Anna Elisabeth

doi:10.1038/srep23116

Cited by 33 publications

(15 citation statements)

References 79 publications

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“…This finding is consistent with the idea that different toxic αSyn strains are present contingent on the differing synucleinopathy clinical and pathologic states (32,33). Furthermore, the current data support the hypothesis that different conformations and/or posttranslational modifications can confer varying degrees of αSyn strain toxicity or infectivity, which may in turn drive the rate of disease progression (10,32,34,35). The potential differences between the discrete αSyn strains have yet to be clearly elucidated.…”

Section: Discussionsupporting

confidence: 89%

Characterization of pathology-inducing α-synuclein species from human diseased brain tissue

Graef

Hoque

Polson

et al. 2019

Preprint

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Synucleinopathies are a group of neurodegenerative diseases characterized by the presence of pathological accumulations of misfolded, phosphorylated α-synuclein (αSyn) protein. Multiple lines of evidence indicate that synucleinopathy disease progression is driven by a prion-like process of transmission of a pathologic form of αSyn. One potential therapeutic approach to prevent cell-to-cell propagation is to target this transmissible species with selective antibodies. In this study, a rodent primary neuronal culture reporter system was developed to monitor induction of detergent-insoluble, phosphorylated (pS129) aggregates of αSyn. Induction of pS129 αSyn pathology was observed with both synthetic αSyn fibrils (PFFs) and brain lysates from multiple system atrophy (MSA) patients but not αSyn monomers or human brain lysate controls. The induction-competent species in MSA lysates could be enriched by high-speed centrifugation suggesting that it is present as a high molecular weight aggregate. Furthermore, samples derived from brain lysates from Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) patients also induced pS129 αSyn pathology, but required longer incubation times. Lastly, the potential of αSyn selective antibodies to immunodeplete induction-competent forms of αSyn from both PFF and synucleinopathy brain samples is described. The results demonstrate that antibodies targeting the C-terminal of αSyn are most effective for immunodepletion of pathology-inducing forms of αSyn from samples derived from human synucleinopathy brains. Furthermore, the data support the hypothesis that antibodies that recognize a C-terminal epitope and exhibit selectivity for oligomeric forms over monomeric forms of αSyn represent a desirable target for immunotherapy for synucleinopathy patients.

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Section: Discussionsupporting

confidence: 89%

Characterization of pathology-inducing α-synuclein species from human diseased brain tissue

Graef

Hoque

Polson

et al. 2019

Preprint

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“…The consensus emerged that oligomers, generated on or off the pathway to amyloid formation or resulting from fibril degradation, are primary players in protein-misfolding toxicity (49)(50)(51)(52). The involvement of pα-syn in PD pathology was recognized exactly two decades ago (10), and numerous studies have examined the morphology and localization of α-syn aggregates (14,53). Recently, the concept has emerged of the existence of different "strains" of α-syn aggregates by analogy to prions, which are aggregates of misfolded prion protein (54,55).…”

Section: Discussionmentioning

confidence: 99%

Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease

Grassi

Howard

Zhou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

180

155

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Exposure of cultured primary neurons to preformed α-synuclein fibrils (PFFs) leads to the recruitment of endogenous α-synuclein and its templated conversion into fibrillar phosphorylated α-synuclein (pα-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. Pα-synF was described previously as inclusions morphologically similar to Lewy bodies and Lewy neurites in PD patients. We discovered the existence of a conformationally distinct, nonfibrillar, phosphorylated α-syn species that we named "pα-syn*." We uniquely describe the existence of pα-syn* in PFF-seeded primary neurons, mice brains, and PD patients' brains. Through immunofluorescence and pharmacological manipulation we showed that pα-syn* results from incomplete autophagic degradation of pα-synF. Pα-synF was decorated with autophagic markers, but pα-syn* was not. Western blots revealed that pα-syn* was N- and C-terminally trimmed, resulting in a 12.5-kDa fragment and a SDS-resistant dimer. After lysosomal release, pα-syn* aggregates associated with mitochondria, inducing mitochondrial membrane depolarization, cytochrome C release, and mitochondrial fragmentation visualized by confocal and stimulated emission depletion nanoscopy. Pα-syn* recruited phosphorylated acetyl-CoA carboxylase 1 (ACC1) with which it remarkably colocalized. ACC1 phosphorylation indicates low ATP levels, AMPK activation, and oxidative stress and induces mitochondrial fragmentation via reduced lipoylation. Pα-syn* also colocalized with BiP, a master regulator of the unfolded protein response and a resident protein of mitochondria-associated endoplasmic reticulum membranes that are sites of mitochondrial fission and mitophagy. Pα-syn* aggregates were found in Parkin-positive mitophagic vacuoles and imaged by electron microscopy. Collectively, we showed that pα-syn* induces mitochondrial toxicity and fission, energetic stress, and mitophagy, implicating pα-syn* as a key neurotoxic α-syn species and a therapeutic target.

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“…Despite the increased knowledge in this field, our understanding of the roles of different α-syn aggregates for the propagation of pathology in Lewy body disorders remains incomplete. However, it has been shown that α-syn aggregates can cause cellular toxicity depending on intracellular locations [21], and evidence suggests detrimental effects on both mitochondrial [22] and lysosomal [19] functions, as well as autophagy [23] and calcium homoeostasis [24]. …”

Section: Introductionmentioning

confidence: 99%

Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes

et al. 2016

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Parkinson’s disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

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Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology

Cited by 33 publications

References 79 publications

Characterization of pathology-inducing α-synuclein species from human diseased brain tissue

Characterization of pathology-inducing α-synuclein species from human diseased brain tissue

Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease

Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes

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