Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

Araki, Kyosuke; Yagi, Naoto; Aoyama, Koki; Choong, Chi‐Jing; Hayakawa, Hideki; Fujimura, Harutoshi; Nagai, Yoshitaka; Goto, Yuji; Mochizuki, Hideki

doi:10.1073/pnas.1906124116

Cited by 122 publications

(130 citation statements)

References 34 publications

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“…We have also shown that the droplet state can undergo a maturation process into a gel-like state rich in amyloid structure, which is reminiscent of the pathological state seen in Lewy body pathologies [14,15,60]. This phenomenon is expected on the grounds that the transition from the droplet state to the amyloid state takes place through a maturation process, known as Ostwald ripening [61,62], and it is consistent with the recent report that a-synuclein can form hydrogels [63,64].…”

Section: Discussionsupporting

confidence: 89%

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Hardenberg

Sinnige

Casford

et al. 2020

Preprint

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Misfolded a-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease. A large body of evidence shows that a-synuclein can self-assemble into amyloid fibrils, but the relationship between amyloid formation and Lewy body formation still remains unclear. Here we show, both in vitro and in a C. elegans model of Parkinson's disease, that a-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies is linked to the arrested maturation of a-synuclein condensates in the presence of lipids and other cellular components.Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting over 2% of the world's population over 65 years of age [1,2]. The molecular origins of this disease are not fully understood, although they have been closely associated with dysregulation of the behaviour of a-synuclein [1, 3, 4], a disordered protein whose function appears to involve the regulation of synaptic vesicle trafficking [5][6][7][8]. This gap in our knowledge of the disease aetiology is no doubt partly responsible for the lack of disease modifying therapies for PD [9][10][11][12].The pathological hallmark of PD is the presence of Lewy bodies within dopaminergic neurons in the brains of affected patients [13]. Although misfolded a-synuclein is a major constituent of Lewy bodies [14,15], ultrastructural and proteome studies have indicated that these aberrant deposits contain a plethora of cellular components, including lipid membranes and organelle fragments [16][17][18][19][20]. These findings have led to the suggestion that the processes associated with the formation of Lewy bodies could be major drivers of neurotoxicity in PD [16,18,21].Since it has also been shown that a-synuclein can aggregate into ordered amyloid fibrils in vitro [22][23][24][25][26] and in vivo [27][28][29][30][31][32], we asked how such a-synuclein aggregation can be reconciled with the formation of highly complex and heterogeneous assemblies such as Lewy bodies. We hypothesised that a-synuclein may be capable of irreversibly capturing cellular components through liquid-liquid phase separation, as this mechanism has been shown to drive the self-assembly of various disease-associated proteins on-pathway to the formation of solid aggregates [33][34][35][36]. Under healthy conditions, the condensation of proteins into a dense liquid droplet state through liquid-liquid phase separation is normally reversible, and exploited in a variety of ways to carry out cellular functions, including RNA metabolism, ribosome biogenesis, DNA damage response and signal transduction [33,34,37]. Upon dysregulation, however, liquid droplets can mature into gel-like deposits, which irreversibly sequester important cellular components and lead to pathological processes [38...

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Section: Discussionsupporting

confidence: 89%

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Hardenberg

Sinnige

Casford

et al. 2020

Preprint

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“…These findings are supported by earlier studies demonstrating the anti-amyloidogenic potential of BME on α-Synuclein [37]. Parkinson's disease is recently being considered as a type of amyloidosis-of which the main neuropathological diagnostic feature is the accumulation of cross-β sheet-rich aggregates of α-Synuclein as Lewy bodies in the brain [38]. The crucial step in the pathogenesis of Parkinson's disease is the aggregation of α-Synuclein [39], which is reportedly attenuated by B. monnieri extract [37].…”

Section: Discussionsupporting

confidence: 82%

Transthyretin Anti-Amyloidogenic and Fibril Disrupting Activities of Bacopa monnieri (L.) Wettst (Brahmi) Extract

2019

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The homotetrameric plasma protein transthyretin (TTR), is responsible for a series of debilitating and often fatal disorders in humans known as transthyretin amyloidosis. Currently, there is no cure for TTR amyloidosis and treatment options are rare. Thus, the identification and development of effective and safe therapeutic agents remain a research imperative. The objective of this study was to determine the effectiveness of Bacopa monnieri extract (BME) in the modulation of TTR amyloidogenesis and disruption of preformed fibrils. Using aggregation assays and transmission electron microscopy, it was found that BME abrogated the formation of human TTR aggregates and mature fibrils but did not dis-aggregate pre-formed fibrils. Through acid-mediated and urea-mediated denaturation assays, it was revealed that BME mitigated the dissociation of folded human TTR and L55P TTR into monomers. ANS binding and glutaraldehyde cross-linking assays showed that BME binds at the thyroxine-binding site and possibly enhanced the quaternary structural stability of native TTR. Together, our results suggest that BME bioactives prevented the formation of TTR fibrils by attenuating the disassembly of tetramers into monomers. These findings open up the possibility of further exploration of BME as a potential resource of valuable anti-TTR amyloidosis therapeutic ingredients.

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“…α-Syn initially localizes to the plasma membrane in yeast, but eventually forms toxic cytoplasmic inclusions that are detergent-insoluble, contain high molecular weight α-syn species, react with the amyloid-diagnostic dye Thioflavin-S, and cluster cytoplasmic vesicles reminiscent of aspects of Lewy pathology in PD (Araki et al, 2019;Gitler et al, 2008;Outeiro and Lindquist, 2003;Shahmoradian et al, 2019;Soper et al, 2008;Tenreiro et al, 2014;Zabrocki et al, 2005). While Hsp104 is unable to antagonize formation of cytoplasmic α-syn foci and return α-syn to the plasma membrane, enhanced variants Hsp104 K358D and Hsp104 K358D:Y257L robustly clear α-syn foci ( Figure 5A, B).…”

Section: α-Syn-specific Hsp104 Variants Differentially Affect Cytoplamentioning

confidence: 99%

“…PD is marked by misfolding of α-synuclein (α-syn), a protein normally found in presynaptic terminals, which may function in synaptic vesicle recycling (Abeliovich and Gitler, 2016;Sun et al, 2019). α-Syn misfolds into toxic oligomers and amyloid fibrils, accumulating in characteristic Lewy bodies in the cytoplasm of dopaminergic neurons that degenerate in PD (Araki et al, 2019;Henderson et al, 2019;Shahmoradian et al, 2019). Indeed, protein misfolding and aggregation unite a spectrum of fatal neurodegenerative diseases (Chuang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

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Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, αsynuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synucleinspecific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

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Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

Cited by 122 publications

References 34 publications

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Transthyretin Anti-Amyloidogenic and Fibril Disrupting Activities of Bacopa monnieri (L.) Wettst (Brahmi) Extract

Tuning Hsp104 specificity to selectively detoxify α-synuclein

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