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Pharmacological inhibition of α-synuclein aggregation within liquid condensates
Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.
- Samuel T. Dada
- , Zenon Toprakcioglu
- & Michele Vendruscolo
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Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes
The aggregation of the neuronal protein α-Synuclein is associated with the onset of Parkinson’s disease. Here the authors report a two-dimensional Fragment Assisted Structure-based technique to find antagonists of α-Synuclein aggregation and show its promise for identifying lead therapeutics for Parkinson’s disease.
- Nicholas H. Stillman
- , Johnson A. Joseph
- & Sunil Kumar
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Tracing genetic diversity captures the molecular basis of misfolding disease
Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management.
- Pei Zhao
- , Chao Wang
- & William E. Balch
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Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2
Maintaining a healthy nuclear proteome during DNA damage is important but its regulation is poorly understood. The authors here show that a SUMO modification of the small heat shock protein Btn2 regulates yeast nuclear protein sequestration during stress.
- Arun Kumar
- , Veena Mathew
- & Peter C. Stirling
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Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus
Modulating amyloid protein phase separation and fibrilization may help in addressing neurodegenerative diseases. This study demonstrates that halogen-doped graphene quantum dots can modulate these processes in TDP-43 in both nucleus and cytoplasm.
- Hong Zhang
- , Huazhang Guo
- & Bin Dai
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Hairpin trimer transition state of amyloid fibril
Amyloid fibrils are ordered protein assemblies implicated in neurodegenerative disease. Here the authors show that hairpin trimers can be transition states of fibril nucleation, explaining how different fibril isoforms may arise from alternative nucleation sites.
- Levent Sari
- , Sofia Bali
- & Milo M. Lin
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Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li
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Diverging co-translational protein complex assembly pathways are governed by interface energy distribution
Protein complex assembly can occur co-translationally. Here, the authors uncover diverging assembly pathways and hotspot disruptions in N-terminal acetyltransferases, enzymes implicated in neurodegenerative diseases. Their model predicts co-translational assembly based on interface energy distribution.
- Johannes Venezian
- , Hagit Bar-Yosef
- & Ayala Shiber
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HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Sheng Chen
- , Anuradhika Puri
- & Meredith E. Jackrel
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A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2
The main protease (Mpro) plays a crucial role in the replication of SARS-CoV-2, thereby making it an attractive target for COVID-19 treatment. Here, the authors develop a colorimetric screening platform for discovering Mpro inhibitors using engineered amyloid peptide-based nanocomplexes.
- Dongtak Lee
- , Hyo Gi Jung
- & Dae Sung Yoon
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Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Mutations in rhodopsin can cause the receptor to aggregate, however, it is unclear whether this molecular defect underlies the retinal degeneration in autosomal dominant retinitis pigmentosa. Here, the authors show the potential for rhodopsin aggregates to play a role in retinal degeneration.
- Sreelakshmi Vasudevan
- , Subhadip Senapati
- & Paul S.–H. Park
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Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis
Here the authors discover a dedicated ribosome-associated chaperone, Chp1, that assists in the challenging biogenesis of eukaryotic translation elongation factor 1A (eEF1A) by cotranslationally stabilizing the growing GTPase domain of eEF1A.
- Melania Minoia
- , Jany Quintana-Cordero
- & Claes Andréasson
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Cryo-EM structures of lipidic fibrils of amyloid-β (1-40)
Alzheimer’s plaques contain a high amount of Aβ fibrils and a high concentration of lipids. The authors determined structures of Aβ40 fibrils grown in the presence of lipids, revealing high-resolution details of potentially disease-relevant fibril-lipid interactions.
- Benedikt Frieg
- , Mookyoung Han
- & Gunnar F. Schröder
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Protein thermal sensing regulates physiological amyloid aggregation
Cells form non-pathological amyloids to survive stressful conditions. Marijan et al. show that heat shock-induced aggregation is self-regulated by protein stability, with high-ordered motifs acting as thermo-switches that control amyloidogenesis.
- Dane Marijan
- , Evgenia A. Momchilova
- & Timothy E. Audas
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Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
In this work, the authors report Cryo-EM imaging revealing diversity in amyloid fibril structures among ATTR patients with the same genetic mutation I84S. Further study is warranted to grasp the implications in ATTR amyloidosis pathology.
- Binh An Nguyen
- , Virender Singh
- & Lorena Saelices
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Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils
This study presents the cryo-EM structures of polymorphic TDP-43-derived amyloid fibrils that share a common fibril protein conformation constituting an amyloid key motif. The obtained results provide a possible mechanistic explanation for the formation of this motif in amyloid fibrils.
- Kartikay Sharma
- , Fabian Stockert
- & Marcus Fändrich
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Nuclear Hsp104 safeguards the dormant translation machinery during quiescence
During aging, proteins are damaged and can misfold, compromising cellular viability. Here, Kohler et al. uncover how aging cells maintain fitness by redirecting the protein repair factor Hsp104 to the nucleus in response to metabolic cues.
- Verena Kohler
- , Andreas Kohler
- & Sabrina Büttner
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Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller
Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
- Emily G. Saccuzzo
- , Mubark D. Mebrat
- & Raquel L. Lieberman
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Prion protein conversion at two distinct cellular sites precedes fibrillisation
In this work, the authors investigated the cellular mode of prion propagation. The report that proteopathic seeds of abnormal PrP are N-terminally truncated and detected within minutes after infection. These seeds reach the plasma membrane by regulated secretory pathways where phenotypically distinct fibril-like PrP aggregates are formed with a lag of 24 h after infection.
- Juan Manuel Ribes
- , Mitali P. Patel
- & Peter-Christian Klöhn
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Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Programmable de novo designed coiled coil-mediated phase separation in mammalian cells
Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. Here the authors design protein liquid condensates from tunable concatenated coiled-coil dimer modules, unraveling the principles for coexisting condensates, chemical regulation, formation from either one or two polypeptide components in mammalian cells.
- Maruša Ramšak
- , Dominique A. Ramirez
- & Roman Jerala
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Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis
Hereditary ATTR amyloidosis has diverse disease manifestations. Using cryo-EM it was possible to reveal, that the phenotypic variations arise from the circumstances under which the amyloid fibrils are formed, rather than from different fibril morphologies.
- Maximilian Steinebrei
- , Julian Baur
- & Marcus Fändrich
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YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner
YTHDF2 has been extensively studied as an m6A-related RNA metabolism. Here, the authors show that YTHDF2 also contributes to protein homeostasis in an m6A-independent manner by promoting the formation of aggresomes through its interaction with UPF1.
- Hyun Jung Hwang
- , Tae Lim Park
- & Yoon Ki Kim
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C3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.
- Xiuhua Yin
- , Hong Zhou
- & Ruhong Zhou
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Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding
Here the authors show that beta-lactamase have an intrinsic aggregation propensity that can be exploited to inactivate these enzymes that mediate antibiotic resistance, using peptides that are based on aggregation prone regions in the sequence of the beta-lactamase.
- Ladan Khodaparast
- , Laleh Khodaparast
- & Joost Schymkowitz
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Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
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Polymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation
In this work, the authors highlight that conserved receptor binding segments of class B GPCR ligands have a dual nature: they serve as amyloid-prone regions involved in pH-dependent conversion from secretory amyloid fibrils to the functional folded form.
- Dániel Horváth
- , Zsolt Dürvanger
- & András Perczel
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Intermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers
High neuronal proteostress can trigger the production of aggregate-filled exophers in C. elegans. Here authors show that such extrusion relies on aggregate-associated intermediate filaments and adaptors.
- Meghan Lee Arnold
- , Jason Cooper
- & Monica Driscoll
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Cryo-EM structure and polymorphic maturation of a viral transduction enhancing amyloid fibril
In this work, the authors report the Cryo-EM structure of PNF-18, a biotechnologically engineered peptide fibril that enhances retroviral infectivity. The peptide fibrils mature into polymorphic amyloid structures in a time-dependent manner. The structure provides insights into the molecular basis of peptide nanofibrils as retroviral transduction enhancers.
- Thomas Heerde
- , Desiree Schütz
- & Marcus Fändrich
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Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction
Mitochondrial dysfunction results in the accumulation of mitochondrial proteins in the cytosol. Here, the authors show that the immunoproteasome subunit PSMB9 promotes protein degradation to maintain cellular protein homeostasis.
- Minji Kim
- , Remigiusz A. Serwa
- & Agnieszka Chacinska
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Fully co-factor-free ClearTau platform produces seeding-competent Tau fibrils for reconstructing pathological Tau aggregates
The authors report a method for producing co-factor-free fibrils from all full-length Tau isoforms. The method paves the way for reconstituting pathology resembling Tau fibrils and enables screening of Tau aggregation-modifying compounds for targeted therapies and PET tracers.
- Galina Limorenko
- , Meltem Tatli
- & Hilal A. Lashuel
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Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005
Using solution-state NMR spectroscopy, the authors followed the individual steps involved in protein misfolding from the native to the amyloid fibril state for the antibody light chain (AL) amyloidosis related protein FOR005.
- Tejaswini Pradhan
- , Riddhiman Sarkar
- & Bernd Reif
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Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments
Understanding the mode of small-molecule binding to amyloid filaments is critical for diagnosing and treating neurodegeneration. The authors use cryo-EM to reveal a stacked binding motif which may hasten design of diagnostics and therapeutics.
- Gregory E. Merz
- , Matthew J. Chalkley
- & Daniel R. Southworth
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Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering
Here the authors report time-resolved experiments showing that amyloid-β peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.
- Jaekyun Jeon
- , Wai-Ming Yau
- & Robert Tycko
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Structural analysis and architectural principles of the bacterial amyloid curli
Using Alpha fold modelling and cryo-EM reconstruction the authors reveal the structural and architectural principles of the bacterial functional amyloid curli, encompassing the continuous stacking of β-solenoid pseudo repeats within and across subunits.
- Mike Sleutel
- , Brajabandhu Pradhan
- & Han Remaut
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| Open Access
Artificial Hsp104-mediated systems for re-localizing protein aggregates
Protein aggregates are a hallmark of neurodegenerative disease and aging. Here, Fischbach et al. report engineered, artificial systems to re-localise or export protein aggregates from cells, with preliminary data showing that mHtt inclusions in S. cerevisiae may be cytotoxic.
- Arthur Fischbach
- , Angela Johns
- & Thomas Nyström
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| Open Access
Cell surface-localized CsgF condensate is a gatekeeper in bacterial curli subunit secretion
In this work, the authors show that the phase separation of a cell surface-associated protein called CsgF is critical to mediate the secretion and assembly of the amyloidogenic curli subunits.
- Hema M. Swasthi
- , Joseph L. Basalla
- & Matthew R. Chapman
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| Open Access
Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.
- Einav Tayeb-Fligelman
- , Jeannette T. Bowler
- & David S. Eisenberg
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| Open Access
Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.
- Rita Rosado-Ramos
- , Gonçalo M. Poças
- & Cláudia N. Santos
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| Open Access
Disease-relevant β2-microglobulin variants share a common amyloid fold
The authors use cryo-EM to determine amyloid fibrils structures of disease relevant variants of β2-microglobulin in vitro. Each variant is polymorphic, but all polymorphs from all samples are built from a a lego-like assembly of common building blocks, suggesting a one amyloid fold’ paradigm.
- Martin Wilkinson
- , Rodrigo U. Gallardo
- & Neil A. Ranson
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| Open Access
Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis
How cells respond to denaturation of extracellular protein domains remained largely unknown. Here, authors describe an aggregation-dependent endocytosis pathway, facilitating uptake and degradation of antibody- and stress-induced protein aggregates.
- David Paul
- , Omer Stern
- & Harvey McMahon
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Spatially confined protein assembly in hierarchical mesoporous metal-organic framework
Immobilization of biomolecules into porous materials could lead to enhanced performance in terms of stability and easier separation for their reuse. Here authors gain insights into the spatial arrangement of green fluorescent protein entrapped in a mesoporous MOF by situ small-angle neutron scattering.
- Xiaoliang Wang
- , Lilin He
- & Shengqian Ma
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| Open Access
Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes
Bhardwaj et al., have explored the proteomes of SARS-CoV and SARS-CoV-2, and have demonstrated the amyloid formation of viral proteins, in vitro, through diverse biophysical techniques.
- Taniya Bhardwaj
- , Kundlik Gadhave
- & Rajanish Giri
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| Open Access
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.
- Itika Saha
- , Patricia Yuste-Checa
- & Mark S. Hipp
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Rabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering
GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in hippocampus and cortex, display distinct organization and mobility in the neuronal surface. Here, authors show Rph3A, a GluN2A-specific binding protein, undergoes liquid-liquid phase separation, which regulate mobility, synaptic and extrasynaptic surface clustering, synaptic localization and synaptic response of GluN2A.
- Lei Yang
- , Mengping Wei
- & Chen Zhang
Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease