Amyloid Fibril Protein Research Articles

Systemic AL amyloidosis presenting with diffuse alveolar septal involvement and respiratory failure: a case report and review of the literature

BackgroundAmyloidosis is the extracellular deposition of amyloid fibril protein in any tissue or organ. The clinical manifestations of pulmonary amyloidosis are variable and without specific symptoms. We report a rare case of diffuse alveolar septal amyloidosis which is an extremely rare pattern of involvement, with a very poor prognosis, to improve our understanding of the disease.Case presentationA 27-year-old man complained of shortness of breath and cyanosis. High-resolution computed tomography revealed diffuse ground-glass opacifications with interlobular septal thickening in both lungs. The immune-histochemistry showed monoclonal lambda light chains. This case also showed nephrotic syndrome and cardiac arrhythmia, suggesting an involvement of the kidney and the heart. Diagnosis: The diagnosis was finally established by tru-cut transthoracic sonar guided lung biopsy (TSLB), and histological examination revealed Congo red-positive amorphous eosinophilic deposits in the alveolar sept. Interventions: The patient was admitted to a respiratory intensive care unit and put on non-invasive ventilation, then discharged on domiciliary oxygen therapy, and started treatment with chemotherapy melphalan 2 mg daily plus prednisone 60 mg daily immediately after the result of histopathology. Outcomes: Three months after treatment, dyspnea and hypoxemia improved, and he continued treatment. The patient was in a good clinical condition after 10 months of follow-up, but he died suddenly.ConclusionAs it is difficult to distinguish diffuse alveolar septal amyloidosis from other interstitial and granulomatous lung diseases because of their similar symptoms and imaging findings, thus, transthoracic sonar guided lung biopsy and histological examination is very important in the diagnosis of diffuse alveolar septal amyloidosis.

The Clinical Impact of Proteomics in Amyloid Typing

The Clinical Impact of Proteomics in Amyloid Typing

Understanding the Formation of Apoferritin Amyloid Fibrils.

We present the optimization of experimental conditions to yield long, rigid apoferritin protein amyloid fibrils, as well as the corresponding fibrillation pathway. Fibril growth kinetics was followed using atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS), circular dichroism (CD), fourier-transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Among the morphologies identified, we show that the conditions result in small aggregates, as well as medium and long fibrils. Extended incubation times led to progressive unfolding and hydrolysis of the proteins into very short peptide fragments. AFM, SDS-PAGE, and CD support a universal common fibrillation mechanism in which hydrolyzed fragments play the central role. These collective results provide convincing evidence that protein unfolding and complete hydrolysis of the proteins into very short peptide sequences are essential for the formation of the final apoferritin amyloid-like fibrils.

Mechanism of misfolding of the human prion protein revealed by a pathological mutation

The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant.

Characterization of iron reducibility of soy protein amyloid fibrils and their applications in iron fortification

Iron deficiency is a common nutritional disorder worldwide. Iron fortification of food is an effective strategy to control iron deficiency anemia (IDA), however, traditional iron fortificants usually provoke undesirable organoleptic changes or have limited colloid stability. In this research, we investigated iron reducibility of soy protein amyloid fibrils made from soy protein isolates (SPI), soy β-conglycinin (7S) and soy glycinin (11S), and explored their applications in iron fortification. All three protein fibrils showed iron reducibility. The reducibility was utilized to generate fibril-iron nanoparticle composites. The iron reducibility was affected by fibril concentration, degree of fibrillation and reducing amino acid composition. We identified 11S had the most significant effect on reducing Fe (III) to more bioavailable Fe (II) state, whereas 7S showed the optimal result for generation of iron nanoparticle on fibrils in situ. The resulted fibril-iron nanoparticle hybrids showed high dispersibility in various liquid foods, without distinct color change.

Mass spectrometry-based proteomic analysis of parathyroid adenomas reveals PTH as a new human hormone-derived amyloid fibril protein

Background Congo red-positive material was described in normal and diseased parathyroids (adenoma and hyperplasia) 50 years ago. However, the incidence and the clinical significance of such observation are unknown, and the causal fibril protein has never been convincingly demonstrated. Methods We conducted the present study including an exceptional case report accompanied with a retrospective study of 105 parathyroid adenomas. We used histopathological, immunohistochemical, ultrastructural, mass spectrometry-based proteomic analysis of parathyroid adenoma tissue samples, and genetic analysis. Results We describe a 57-year-old man with mild hypercalcemia and elevated parathyroid hormone (PTH) level for whom histopathological analysis revealed a parathyroid adenoma associated with nodular typical amyloid deposits. Tandem mass spectrometry after laser microdissection (LMD-MS) of amyloid adenoma identified PTH as the fibril protein, and no germline mutation in the PTH gene was detected. Congo red-positive PTH-deposits were further observed in 6.6% of the parathyroid adenomas analyzed, and were associated with complete/incomplete or absent universal amyloid signature, but with fibrillar morphology at ultrastructural level. Conclusions Inappropriate PTH production leads to progressive disease-amyloid aggregation of PTH in a subset of parathyroid adenomas, providing new insights into the pathophysiology of this condition and adding PTH to the list of amyloid protein derived from hormones.

Apoferritin Amyloid-Fibril Directed the In Situ Assembly and/or Synthesis of Optical and Magnetic Nanoparticles

The coupling of proteins that can assemble, recognise or mineralise specific inorganic species is a promising strategy for the synthesis of nanoscale materials with a controllable morphology and functionality. Herein, we report that apoferritin protein amyloid fibrils (APO) have the ability to assemble and/or synthesise various metal and metal compound nanoparticles (NPs). As such, we prepared metal NP–protein hybrid bioconjugates with improved optical and magnetic properties by coupling diverse gold (AuNPs) and magnetic iron oxide nanoparticles (MNPs) to apoferritin amyloid fibrils and compared them to the well-known β-lactoglobulin (BLG) protein. In a second approach, we used of solvent-exposed metal-binding residues in APO amyloid fibrils as nanoreactors for the in situ synthesis of gold, silver (AgNPs) and palladium nanoparticles (PdNPs). Our results demonstrate, the versatile nature of the APO biotemplate and its high potential for preparing functional hybrid bionanomaterials. Specifically, the use of apoferritin fibrils as vectors to integrate magnetic MNPs or AuNPs is a promising synthetic strategy for the preparation of specific contrast agents for early in vivo detection using various bioimaging techniques.

Cross-seeding of alpha-synuclein aggregation by amyloid fibrils of food proteins

The aggregation of the protein α-synuclein (aSyn) into amyloid fibrils in the human brain is associated with the development of several neurodegenerative diseases, including Parkinson's disease. The previously observed prion-like spreading of aSyn aggregation throughout the brain and the finding that heterologous cross-seeding of amyloid aggregation occurs in vitro for some proteins suggest that exposure to amyloids in general may pose a risk for disease development. To elucidate which protein fibril characteristics determine if and how heterologous amyloid seeding can occur, we investigated the potential of amyloid fibrils formed from proteins found in food, hen egg white lysozyme, and bovine milk β-lactoglobulin to cross-seed aSyn aggregation in the test tube. We observed that amyloid fibrils from lysozyme, but not β-lactoglobulin, potently cross-seeded the aggregation of aSyn as indicated by a significantly shorter lag phase of aSyn aggregation in the presence of lysozyme fibrils. The cross-seeding effect of lysozyme was found to be primarily driven by a surface-mediated nucleation mechanism. The differential seeding effect of lysozyme and β-lactoglobulin on aSyn aggregation could be explained on the basis of binding affinity, binding site, and electrostatic interactions. Our results indicate that heterologous seeding of proteins may occur depending on the physicochemical characteristics of the seed protein fibril. Our findings suggest that heterologous seeding has the potential to determine the pathogenesis of neurodegenerative amyloid diseases.

Concentration-dependent influence of silver nanoparticles on amyloid fibrillation kinetics of hen egg-white lysozyme

Understanding the influence of nanoparticles on the formation of protein amyloid fibrillation is crucial to extend their application in related biological diagnosis and nanomedicines. In this work, Raman spectroscopy was used to probe the amyloid fibrillation of hen egg-white lysozyme in the presence of silver nanoparticles (Ag-NPs) at different concentrations, combined with atomic force microscopy and thioflavin T (ThT) fluorescence assays. Four representative Raman indicators were utilized to monitor transformation of the protein tertiary and secondary structures at the molecular level: the Trp doublet bands at 1340 and 1360 cm−1, the disulfide stretching vibrational peak at 507 cm−1, the N-Cα-C stretching vibration at 933 cm−1, and the amide I band. All experimental results confirmed the concentration-dependent influence of AgNPs on the hen egg-white lysozyme amyloid fibrillation kinetics. In the presence of AgNPs at low concentration (17 µg/mL), electrostatic interaction of the nanoparticles stabilizes disulfide bonds, and protects the Trp residues from exposure to hydrophilic environment, thus leading to formation of amorphous aggregates rather than fibrils. However, with the action of AgNPs at high concentration (1700 µg/mL), the native disulfide bonds of hen egg-white lysozyme are broken to form Ag-S bonds owing to the competition of electrostatic interaction from a great deal of nanoparticles. As for providing functional surfaces for protein to interact with, AgNPs play a bridge role in direct transformation from α-helices to organized β-sheets. The present investigation sheds light on the controversial effects of AgNPs on the kinetics of hen egg-white lysozyme amyloid fibrillation.

Renal Amyloidosis With a Frame Shift Mutation in Fibrinogen Aα-Chain Gene Producing a Novel Amyloid Protein

AbstractA French kindred with autosomal dominant hereditary renal amyloidosis was found to have a novel mutation in the fibrinogen Aα-chain gene. In this kindred, renal disease appeared early in life and led to terminal renal failure at an early age. Renal transplantation resulted in rapid destruction of the allograft by amyloid deposition within 2 years. Amyloid fibril protein isolated from a transplanted kidney was found to contain a novel, hybrid peptide of 49 residues whose N-terminal 23 amino acids were identical to residues 499 to 521 of normal fibrinogen Aα-chain. The remainder of the peptide (26 residues) represented a completely new sequence for mammalian proteins. DNA sequencing documented that the new sequence was the result of a single nucleotide deletion at position 4897 of the fibrinogen Aα-chain gene that gives a frame-shift at codon 522 and premature termination at codon 548. The contributions toward fibrillogenesis of the two portions of the amyloid fibril protein, ie, N-terminal fibrinogen sequence and C-terminal novel sequence, are presently unknown. However, the early onset and rapid reoccurrence of amyloid in renal transplants is unlike the clinical course with other amyloid proteins having single amino acid substitutions that give hereditary renal amyloidosis. Liver transplantation to stop synthesis of this abnormal hepatic derived protein should be considered early in the course of the disease.

Immunoglobulin D Myeloma and Amyloidosis: Immunochemical and Structural Studies of Bence Jones and Amyloid Fibrillar Proteins

Urinary Bence Jones protein and amyloid fibril protein isolated from the subcutaneous tissue of a patient with IgD myeloma and associated amyloidosis were subjected to physicochemical and immunochemical identification. Peptide maps and amino-terminal tetrapeptide composition obtained from the two proteins were comparable. Immunochemical cross-reactivity between the two proteins, with other lambda-type amyloid and Bence Jones proteins, and with a serum component was demonstrated. The results suggest that the source of the amyloid fibril protein is an intact circulating light polypeptide chain as well as smaller amino-terminal fragments.

PCV5 Clinical Characteristics of Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in France: EPACT, a Study Based on the French Nationwide Claims Database Snds

Transthyretin (TTR) Amyloid Cardiomyopathy (ATTR-CM) is a rare, progressively debilitating, fatal disease caused by the deposition of amyloid fibrils of the serum TTR protein in the extracellular matrix of target organs such as the heart. We aimed at describing clinical characteristics of ATTR-CM individuals in France. A cohort of individuals diagnosed with ATTR-CM between 2011 and 2017 was constituted using real-world data from the SNDS nationwide database, which collects health insurance claims and hospital discharge information from 99% of the French population. Their medical characteristics were identified over the 2007-2017 period through long-term disease codes, hospital discharge diagnosis codes and therapeutic procedures. 4815 patients were identified (mean age of 78.7 (10.0) years old, 66.9% of men). Codes and/or procedures related to arrhythmia or conduction disorders, heart failure, and cardiomyopathies were found in the history of 86.3%, 81.0% and 62.7% of patients, respectively. 68.4% of the individuals were affected with other cardiac conditions including non-rheumatoid valvulopathy for 21.7% and aortic stenosis for 18.0%. Concerning the non-cardiac conditions which belong to the amyloidosis clinical spectrum, 18.8% and 13.4% of the included individuals were treated at least once for carpal tunnel syndrome and neurological disorders, respectively, over the 2007-2017 period. A median of 30.7 months elapsed between the appearance of the first event related to the disease – a cardiac event for 85.4% of individuals - and ATTR-CM diagnosis date (date on which a diagnosis of amyloidosis and cardiac damage related to transthyretin cardiac amyloidosis was identified), indicating the complexity of the disease and the difficulty in establishing early a diagnosis of ATTR-CM. ePACT is the first study using a nationwide real-world data to describe the medical features of individuals with ATTR-CM; results are consistent with those already published worldwide on smaller patient cohorts.

Polymorphism of Amyloid Fibrils Induced by Catalytic Seeding: A Vibrational Circular Dichroism Study.

Amyloidal protein fibrils occur in many biological events, but their formation and structural variability are understood rather poorly. We systematically explore fibril polymorphism for polyglutamic acid (PGA), insulin and hen egg white lysozyme. The fibrils were grown in the presence of "seeds", that is fibrils of the same or different protein. The seeds in concentrations higher than about 5 % of the total protein amount fully determined the structure of the final fibrils. Fibril structure was monitored by vibrational circular dichroism (VCD) spectroscopy and other techniques. The VCD shapes significantly differ for different fibril samples. Infrared (IR) and VCD spectra of PGA were also simulated using density functional theory (DFT) and a periodic model. The simulation provides excellent basis for data interpretation and reveals that the spectral shapes and signs depend both on fibril length and twist. The understanding of fibril formation and interactions may facilitate medical treatment of protein misfolding diseases in the future.

The Hematologist's Role in Amyloidosis Management: Disease Awareness, Diagnostic Workup, and Practice Patterns

Introduction: Systemic amyloidoses are progressive, life-threatening diseases characterized by the deposition of amyloid protein fibrils of varying origin in different tissues/organ systems (Merlini G, et al. N Engl J Med 2003;349:583-96). The precursor amyloidogenic protein influences the disease's clinical course, and identification of the specific protein is essential because treatment varies substantially by subtype. While there are 36 known proteins that can aggregate as amyloid in humans (Benson MD, et al. Amyloid 2018;25:215-9), the two most prevalent protein subtypes causing cardiac amyloidosis are derived from immunoglobulin light chains (AL) and transthyretin (ATTR) (Kittleson MM, et al. Circulation 2020;141:e7-22). Both AL and ATTR subtypes often infiltrate the heart, resulting in a restrictive cardiomyopathy along with other multiorgan involvement. Appropriate classification, early identification, and prompt treatment may substantially improve clinical outcomes. Because AL disease occurs in the context of plasma cell dyscrasia, hematologists can play an important role in amyloidosis suspicion, diagnostic workup, and management. However, differentiation of AL and ATTR amyloidoses in patients with signs of cardiac dysfunction is often challenging, and a multidisciplinary approach, including referral to cardiologists, is recommended early in the patient diagnostic workup. To gain insights into hematologists' disease awareness and practices, we interviewed hematologists involved in amyloidosis patient care across the US. Methods: A qualitative double-blind telephone survey was conducted between November 2019 and February 2020 of US hematologists who had diagnosed and/or treated at least 2 patients with AL amyloidosis over the past 2 years. The participants differed based on their experience in various clinical practice settings, including community hospital and private practices, academic institutions, and amyloidosis centers. Results: A total of 16 hematologists participated in the survey (community hospital, n=3; community private practice, n=5; academic institution, n=3; amyloidosis center, n=5). Hematologists at amyloidosis/academic centers (AAC) reported that the AL amyloidosis patient's journey typically involved visits to multiple primary care physicians and specialists in the community over a prolonged period (approximately 1 to 1.5 years) before the patient received a diagnosis (Figure [A]). Community specialists' referrals to academic physicians within the same specialty, due to lack of familiarity with amyloidosis centers, contributed in part to the delay. Several differences were found between hematologists in the community and those at AAC in level of disease awareness and referral/testing practices (Table; Figure [B]). Hematologists in community practice were less likely to be aware of ATTR amyloidosis, refer patients with suspected amyloid to cardiologists, or conduct recommended screening/diagnostic testing. In contrast, hematologists at AAC were highly aware of ATTR amyloidosis, collaborated closely with cardiologists, and used recommended amyloidosis tests. Across practice settings, hematologists consistently conducted biopsies of bone marrow and fat pad in patients with suspected AL amyloidosis to confirm the presence of amyloid. After amyloid was confirmed with Congo red staining, 75% of community hematologists discontinued testing, without establishing the amyloid protein subtype; hematologists at AAC consistently assessed amyloid protein subtype using immunohistochemistry and/or mass spectrometry to differentiate AL and ATTR prior to initiating treatment. Diagnostic algorithms supporting AL and ATTR differentiation were consistently in place and followed at AAC but not in community-based practices. Conclusions: Disease awareness, referral practices, and screening/testing procedures can differ between hematologists in the community setting and those in AAC. Community hematologists may benefit from additional education and wider use of diagnostic algorithms on AL/ATTR amyloidosis. Reinforcing the importance of cardiology referral and guidance on best practices for screening/biopsies/subtyping in patients with suspected amyloidosis who have cardiac symptoms should be prioritized. Disclosures D'Souza: Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Costa Chase:Celgene: Speakers Bureau. Borham:Pfizer: Current Employment, Current equity holder in publicly-traded company. Bruno:Pfizer: Current Employment, Current equity holder in publicly-traded company.

The role of amyloid fibrils in the modification of whey protein isolate gels with the form of stranded and particulate microstructures

Adding fibers to hydrogels is a modern strategy for producing tough hydrogels. Nanofibers usually perform well in hydrogels due to their unique properties. The purpose of this study was to investigate the effects of whey protein amyloid fibril (WPF) on the properties ofheat-set whey proteinisolate (WPI)gels with fine-stranded or particulate microstructure (at pH 7). The results show that by adding WPF, a homogenous and dense network was observed in fine-stranded gel, while the formation of a coarse and amorphous structure with microphase separation intensified in particulate gel. By adding 1% WPF, the elastic modulus of gels increased about 10.6 and 3.6 times in the case of fine-stranded and particulate gels, respectively. In fine-stranded gels, adding WPF to the gel led to a decrease in the Tg value (from 66.33 to 59.36 °C) and a decrease in tan δ (from 0.2328 to 0.0837), indicating an increase in gel strength because of WPF. In contrast, adding WPF to particulate gels did not cause significant changes in the Tg and tan δ. There was a decrease in the water holding property of particulate gels when WPF was added, whereas it did not change significantly in fine-stranded gels. These findings imply that the efficiency of WPF in WPI gels depends not only on the WPF concentration but also on the type of the WPI gel. In sum, WPF enhances order in the structural network of fine-stranded gels, while accelerating the formation of inhomogeneous random aggregates in particulate gels. Creating fiber-hydrogels with different microstructures and rheological properties can be possible by controlling WPI aggregation (as in amyloid fibril, fine-strand or particulate aggregates).

13C and 15N chemical shift assignments of A117V and M129V human Y145Stop prion protein amyloid fibrils.

The C-terminally truncated Y145Stop variant of prion protein (PrP23-144) has been linked to a heritable prionopathy in humans and is also capable of triggering a transmissible prion disease in mice. PrP23-144 can be converted from soluble monomeric form to amyloid under physiological conditions, providing an in vitro model for investigating the molecular basis of amyloid strains and cross-seeding barriers. Here, we use magic-angle spinning solid-state NMR to establish the sequential backbone and sidechain 13C and 15N chemical shift assignments for amyloid fibrils formed by the A117V and M129V mutants of human PrP23-144, which in the context of full length PrP in vivo are among the specific residues associated with development of Gerstmann-Straüssler-Scheinker disease. The chemical shift data are utilized to identify amino acids comprising the rigid amyloid core regions and to predict the protein secondary structures for human PrP23-144 A117V and M129V fibrils.

CARDIAC AA AMYLOIDOSIS SECONDARY TO FAMILIAL MEDITERRANEAN FEVER PRESENTING AS INTERMITENT COMPLETE HEART BLOCK: A RARE CASE WITH LITERATURE REVIEW

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Cardiac amyloidosis is rare but relatively more frequently seen with ATTR and AL types of amyloidosis. AA amyloidosis related cardiomyopathy or conduction abnormalities are rare owing to less frequent involvement of the myocardium in AA amyloidosis. We present a case of complete heart block in the setting of AA amyloidosis secondary to familial mediterranean fever. CASE PRESENTATION: A 50-year-old female with history of familial mediterranean fever (FMF) presented with syncopal episode. On presentation patient's vitals were stable, labs including TSH were within normal limits. Orthostatic vitals were positive. High-sensitivity troponins were negative with a normal EKG on presentation. Laterally displaced apical beat was noticed on examination. During hospitalization patient was noticed to have complete heart block that was not responsive to atropine and transcutaneous pacing however a response was noticed with epinephrine drip. TTE revealed heart failure with reduced ejection fraction of 41% with severe concentric left ventricular thickening typical for amyloid cardiomyopathy with a well-preserved E/A-wave, which is not usually seen in as thickened ventricle as patients. CRP and SAA were elevated. Patient had endomyocardial biopsy that confirmed amyloid deposition staining positive for amyloid AA and negative for TTR, kappa and lambda and a technetium pyrophosphate scan was also negative. A biventricular pacemaker was placed for complete heart block without adequate escape rhythm, which resulted in resolution of episodes of dizziness associated with bradycardia. Patient's FMF was managed with colchicine and anakinra with the help of rheumatology. Patient was started on diuresis during hospitalization and continued on discharge. Patient followed up with amyloidosis clinic after discharge. DISCUSSION: Systemic amyloidosis is rare and results from deposition of amyloid deposits in various organs and hence a wide range of effects. Prognosis may be vary with the type and extent of amyloidosis. More than 95% of cardiac amyloidosis is secondary to light chain/AL amyloidosis or transthyretin amyloidosis (ATTR), both genetic/hereditary and wild type.[1] Cardiac involvement from AA amyloidosis is very rare. Cardiac amyloidosis usually manifests with syncope or postural hypotension, which may be related with bradyarrhythmias.[2] Like the involvement of cardiovascular system, developments of arrhythmias are also common with ATTR type of amyloidosis as compared to other types and may require pacemaker placement. AA cardiac amyloidosis is rare and bradyarrhythmias or conduction system involvement has also been rarely reported. We report a rare case of complete heart block secondary to AA amyloidosis from familial Mediterranean fever requiring pacemaker placement. CONCLUSIONS: We present cardiac AA amyloidosis as a rare cause of syncope and orthostatic hypotension. Reference #1: Sipe, J.D., et al., Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid, 2016. 23(4): p. 209-213. Reference #2: Chamarthi, B., et al., Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol, 1997. 80(9): p. 1242-5 DISCLOSURES: No relevant relationships by Usama Talib, source=Web Response

Modulation of Amyloid Protein Fibrillation by Synthetic Polymers: Recent Advances in the Context of Neurodegenerative Diseases

Protein misfolding and aggregation have attracted immense research interests due to their connection with an array of degenerative diseases including neurodegenerative disorders and non-neuropathic diseases. Inhibition or diminution of the formation of protein aggregates is considered as a potential therapeutic strategy to cure these debilitating maladies. A large number of compounds including flavonoids, surfactants, osmolytes, vitamins, nanoparticles, etc. have been explored for impeding protein aggregation process and ameliorating neurodegenerative disorders. Even though a plethora of strategies have been designed to suppress protein aggregation, the final success rate is limited due to the lack of in-depth understanding of the aggregation pathway. In this context, polymeric materials are attracting the attention of researchers owing to their multifarious applications in the field of biomedical science and technology, and their unique properties as many parameters like functionality, molecular weight, architecture, etc. can be easily manipulated to improve their efficacy as well as meet clinical requirements. This review article highlights an outline of protein misfolding and aggregation, their mechanistic pathway, the factors responsible for aggregation, and potential therapeutic strategies for the intervention of those debilitating pathological conditions. Especially, the primary focus of this review article is to delineate the obligatory role of polymeric materials on protein aggregation pathway and encourage researchers to fabricate effective polymeric materials for designing next generation antiamyloidogenic therapeutic agents.

The Division of Amyloid Fibrils: Systematic Comparison of Fibril Fragmentation Stability by Linking Theory with Experiments.

SummaryThe division of amyloid protein fibrils is required for the propagation of the amyloid state and is an important contributor to their stability, pathogenicity, and normal function. Here, we combine kinetic nanoscale imaging experiments with analysis of a mathematical model to resolve and compare the division stability of amyloid fibrils. Our theoretical results show that the division of any type of filament results in self-similar length distributions distinct to each fibril type and the conditions applied. By applying these theoretical results to profile the dynamical stability toward breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from α-synuclein when compared with non-disease associated model amyloid, the former showing lowered intrinsic stability toward breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments' intrinsic dynamic stabilities, which are key to unraveling their toxic and infectious potentials.

A droplet reactor on a super-hydrophobic surface allows control and characterization of amyloid fibril growth

Methods to produce protein amyloid fibrils, in vitro, and in situ structure characterization, are of primary importance in biology, medicine, and pharmacology. We first demonstrated the droplet on a super-hydrophobic substrate as the reactor to produce protein amyloid fibrils with real-time monitoring of the growth process by using combined light-sheet microscopy and thermal imaging. The molecular structures were characterized by Raman spectroscopy, X-ray diffraction and X-ray scattering. We demonstrated that the convective flow induced by the temperature gradient of the sample is the main driving force in the growth of well-ordered protein fibrils. Particular attention was devoted to PHF6 peptide and full-length Tau441 protein to form amyloid fibrils. By a combined experimental with the molecular dynamics simulations, the conformational polymorphism of these amyloid fibrils were characterized. The study provided a feasible procedure to optimize the amyloid fibrils formation and characterizations of other types of proteins in future studies.