Effect of nitroderivatives of fullerene C60 on amyloid fibrils of the brain Aβ(1–42) peptide and muscle X-protein

AbstractPathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains.

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Drosophila Fragile X Protein, DFXR, Regulates Neuronal Morphology and Function in the Brain

Neuron ◽

10.1016/s0896-6273(02)00731-6 ◽

2002 ◽

Vol 34 (6) ◽

pp. 961-972 ◽

Cited By ~ 155

Author(s):

Joannella Morales ◽

P.Robin Hiesinger ◽

Andrew J. Schroeder ◽

Kazuhiko Kume ◽

Patrik Verstreken ◽

...

Keyword(s):

Fragile X ◽

Neuronal Morphology ◽

X Protein ◽

And Function ◽

The Brain

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Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

Protein Engineering Design and Selection ◽

10.1093/protein/gzz021 ◽

2019 ◽

Vol 32 (2) ◽

pp. 59-66

Author(s):

Sandra Rocha ◽

Ranjeet Kumar ◽

Istvan Horvath ◽

Pernilla Wittung-Stafshede

Keyword(s):

Synaptic Vesicles ◽

Amyloid Fibrils ◽

Membrane Surface ◽

Amyloid Formation ◽

Wild Type ◽

Membrane Affinity ◽

Axis Parallel ◽

Biophysical Techniques ◽

Small Unilamellar Vesicles ◽

The Brain

Abstract α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson’s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906124116 ◽

2019 ◽

Vol 116 (36) ◽

pp. 17963-17969 ◽

Cited By ~ 24

Author(s):

Katsuya Araki ◽

Naoto Yagi ◽

Koki Aoyama ◽

Chi-Jing Choong ◽

Hideki Hayakawa ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Amyloid Fibrils ◽

Lewy Bodies ◽

X Ray Diffraction ◽

Thin Sections ◽

X Ray ◽

Β Sheet ◽

The Brain

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

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In situ architecture of neuronal α-Synuclein inclusions

10.1101/2020.08.07.234138 ◽

2020 ◽

Author(s):

Victoria A. Trinkaus ◽

Irene Riera-Tur ◽

Antonio Martínez-Sánchez ◽

Felix J.B. Bäuerlein ◽

Qiang Guo ◽

...

Keyword(s):

Amyloid Fibrils ◽

Electron Tomography ◽

Structural Flexibility ◽

Multiple Systems ◽

Cryo Electron Tomography ◽

Multiple Systems Atrophy ◽

The Brain ◽

Cellular Organelles

Summaryα-Synuclein (α-Syn) aggregation is a hallmark of devastating neurodegenerative disorders including Parkinson’s disease (PD) and multiple systems atrophy (MSA)1,2. α-Syn aggregates spread throughout the brain during disease progression2, suggesting mechanisms of intercellular seeding. Formation of α-Syn amyloid fibrils is observed in vitro3,4 and fibrillar α-Syn has been purified from patient brains5,6, but recent reports questioned whether disease-relevant α-Syn aggregates are fibrillar in structure7-9. Here we use cryo-electron tomography (cryo-ET) to image neuronal Lewy body-like α-Syn inclusions in situ at molecular resolution. We show that the inclusions consist of α-Syn fibrils crisscrossing a variety of cellular organelles such as the endoplasmic reticulum (ER), mitochondria and autophagic structures, without interacting with membranes directly. Neuronal inclusions seeded by recombinant or MSA patient-derived α-Syn aggregates have overall similar architecture, although MSA-seeded fibrils show higher structural flexibility. Using gold-labeled seeds we find that aggregate nucleation is predominantly mediated by α-Syn oligomers, with fibrils growing unidirectionally from the seed. Our results conclusively demonstrate that neuronal α-Syn inclusions contain α-Syn fibrils intermixed with cellular membranes, and illuminate the mechanism of aggregate nucleation.

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Copper stabilizes antiparallel β-sheet fibrils of the amyloid β40 (Aβ40)-Iowa variant

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011955 ◽

2020 ◽

Vol 295 (27) ◽

pp. 8914-8927

Author(s):

Elliot J. Crooks ◽

Brandon A. Irizarry ◽

Martine Ziliox ◽

Toru Kawakami ◽

Tiffany Victor ◽

...

Keyword(s):

Blood Vessels ◽

Amyloid Fibrils ◽

Brain Parenchyma ◽

Amyloid Peptide ◽

Amyloid Angiopathy ◽

Seeded Growth ◽

Amyloid Deposits ◽

Aβ42 Peptide ◽

Β Sheet ◽

The Brain

Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue–long β-amyloid peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.

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Modulation of ϐ-amyloid production and fibrillization

Biochemical Society Symposium ◽

10.1042/bss0670001 ◽

2001 ◽

Vol 67 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

David Allsop ◽

Lance J. Twyman ◽

Yvonne Davies ◽

Susan Moore ◽

Amber York ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Fibrils ◽

Senile Plaques ◽

Neurofibrillary Tangle ◽

Neuronal Loss ◽

Brain Parenchyma ◽

Amino Acid Peptide ◽

Close Relatives ◽

The Brain

Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as ϐ-amyloid or Aϐ. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of Aϐ in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of Aϐ production and fibrillization.

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Therapeutic Advancement in Alzheimer Disease: New Hopes on the Horizon?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180627122448 ◽

2018 ◽

Vol 17 (8) ◽

pp. 571-589 ◽

Cited By ~ 12

Author(s):

Ajeet Singh ◽

Abshar Hasan ◽

Sakshi Tiwari ◽

Lalit M. Pandey

Keyword(s):

Alzheimer Disease ◽

Mitochondrial Dysfunction ◽

Amyloid Fibrils ◽

Antioxidant Response ◽

Synaptic Activity ◽

Therapeutic Approaches ◽

Ongoing Research ◽

Target Molecules ◽

Developed World ◽

The Brain

Background & Objective: Over the last two decades, Alzheimer disease (AD) associated research has accomplished an overwhelming momentum, as it is one of the major current healthcare issues in the developed world. AD is characterized by the presence of Aβ mediated extracellular amyloid fibrils and tau-mediated intracellular neurofibrillar tangles and reports have highlighted their subsequent effects on neuronal synaptic activity, antioxidant response and recently explored mitochondrial dysfunction. Additionally, recent reports have demonstrated the mitochondrial dysfunction and associated physiological as well as cellular alterations triggered by fibrillar structures inside the brain tissue. Accumulated evidence indicated that mitochondrial dysfunction also plays a detrimental role in AD pathogenesis and reduction in mitochondrial dysfunction may provide an additional beneficial effect in AD patients. Currently available drugs are ineffective in disease progression and more symptomatic while mechanism oriented drug explorations have been intensively investigated. Therefore, search for effective therapeutic approaches in Alzheimer disease has directed the ongoing research more towards specific biomarker selection, physicochemical properties of drugs and its subsequent interaction with target molecules. Conclusion: In present review, we have comprised an overview of the therapeutic advancement in Alzheimer disease with a prevalent hypothesis and current ongoing putative therapeutic approaches to provide recent insights in AD pathogenesis.

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Effects of Pulsed Electric Fields on Yeast with Prions and the Structure of Amyloid Fibrils

Applied Sciences ◽

10.3390/app11062684 ◽

2021 ◽

Vol 11 (6) ◽

pp. 2684

Author(s):

Justina Jurgelevičiūtė ◽

Nedas Bičkovas ◽

Andrius Sakalauskas ◽

Vitalij Novickij ◽

Vytautas Smirnovas ◽

...

Keyword(s):

Electric Field ◽

Electric Fields ◽

Electrostatic Interactions ◽

Amyloid Fibrils ◽

Translation Termination ◽

Yeast Prions ◽

Amyloid Aggregates ◽

Perfect Model ◽

Noncovalent Bonds ◽

The Brain

Prions are misfolded, self-replicating, and transmissible proteins capable of causing different conditions that affect the brain and nervous system in humans and animals. Yeasts are the perfect model to study prion formation, dissemination, and the structure of protein aggregates. Yeast prions are related to stress resistance, cell fitness, and viability. Applying a pulsed electric field (PEF) as a factor capable of disintegrating the amyloid aggregates arises from the fact that the amyloid aggregates form via noncovalent bonds and stabilize via electrostatic interactions. In this research, we applied 2–26 kV/cm PEF delivered in sequences of 5 pulses of 1 ms duration to the Saccharomyces cerevisiae cell without prions and containing strong and weak variants of the [PSI+] prion (prion form of Sup35 translation termination factor). We determined that prions significantly increase cell survivability and resistance to PEF treatment. The application of PEF to the purified Sup35NM fibrils showed that the electric field causes significant reductions in the length of fibrils and the full disintegration of fibrils to Sup35 oligomers can be achieved in higher fields.

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