scholarly journals Confirming the Diagnosis of Amyloidosis

2020 ◽  
Vol 143 (4) ◽  
pp. 312-321
Author(s):  
Brendan Wisniowski ◽  
Ashutosh Wechalekar
Keyword(s):  
Amyloid Fibrils ◽  
General Term ◽  
Disease Phenotype ◽  
Transthyretin Amyloidosis ◽  
Amyloidogenic Proteins ◽  
Amyloidogenic Protein ◽  
Precursor Proteins ◽  
Laser Capture ◽  
Disease Specific ◽  
Over Time

Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many cases, death. Amyloid fibrils are derived from soluble precursor proteins, with the number of known amyloidogenic proteins increasing over time. The identity of the precursor protein often predicts the disease phenotype, although many of the amyloidoses have overlapping clinical features. Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis. Cardiac transthyretin amyloidosis, however, may be diagnosed without a biopsy provided stringent criteria are met. Where amyloid is confirmed histologically, the identity of the amyloidogenic protein must be determined, given several of the amyloidoses have disease-specific therapies. Laser capture microdissection and tandem mass spectrometry, LCM-MS, has revolutionised amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry. Here we summarise the biopsy approach to amyloidosis, as well as the non-biopsy diagnosis of cardiac transthyretin amyloidosis. Proteomic and antibody-based methods for amyloid subtyping are reviewed. Finally, an algorithm for confirming the diagnosis of amyloidosis is presented.

Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure

2019 ◽  
Vol 26 (16) ◽  
pp. 2865-2878 ◽  
Author(s):  
Klemens Ablasser ◽  
Nicolas Verheyen ◽  
Theresa Glantschnig ◽  
Giulio Agnetti ◽  
Peter P. Rainer
Keyword(s):  
Cardiac Disease ◽  
Cardiac Remodeling ◽  
Cardiac Amyloidosis ◽  
Amyloid Fibrils ◽  
Amyloid Deposition ◽  
Transthyretin Amyloidosis ◽  
Cardiac Amyloid ◽  
Amyloidogenic Proteins ◽  
Preclinical Trials ◽  
Current Therapies

Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR.

Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease

2020 ◽  
Vol 477 (9) ◽  
pp. 1721-1732
Author(s):  
Isabelle C. Romine ◽  
R. Luke Wiseman
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Amyloid Fibrils ◽  
Therapeutic Potential ◽  
Peripheral Target ◽  
Disease Pathogenesis ◽  
Amyloid Disease ◽  
Amyloidogenic Proteins ◽  
Amyloidogenic Protein ◽  
Amyloid Diseases

Systemic amyloid diseases are characterized by the deposition of an amyloidogenic protein as toxic oligomers and amyloid fibrils on tissues distal from the site of protein synthesis. Traditionally, these diseases have been viewed as disorders of peripheral target tissues where aggregates are deposited, and toxicity is observed. However, recent evidence highlights an important role for endoplasmic reticulum (ER) proteostasis pathways within tissues synthesizing and secreting amyloidogenic proteins, such as the liver, in the pathogenesis of these disorders. Here, we describe the pathologic implications of ER proteostasis and its regulation on the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Furthermore, we discuss the therapeutic potential for targeting ER proteostasis to reduce the secretion and toxic aggregation of amyloidogenic proteins to mitigate peripheral amyloid-associated toxicity involved in the onset and progression of systemic amyloid diseases.

scholarly journals Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pijush Chakraborty ◽  
Gwladys Rivière ◽  
Shu Liu ◽  
Alain Ibáñez de Opakua ◽  
Rıza Dervişoğlu ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Corticobasal Degeneration ◽  
Binding Studies ◽  
Rigid Core ◽  
Tau Aggregation ◽  
The Brain ◽  
Tau Aggregate ◽  
Disease Specific ◽  
Tau Fibrils

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.

scholarly journals Cardiac Amyloidosis: A Review of Current Imaging Techniques

2021 ◽  
Vol 8 ◽  
Author(s):  
Yousuf Razvi ◽  
Rishi K. Patel ◽  
Marianna Fontana ◽  
Julian D. Gillmore
Keyword(s):  
Bone Scintigraphy ◽  
Cardiac Amyloidosis ◽  
Tissue Characterization ◽  
Amyloid Fibrils ◽  
Imaging Techniques ◽  
Significant Proportion ◽  
Disease Process ◽  
Heterogenous Group ◽  
Pathological Disease ◽  
Over Time

Systemic amyloidosis is a rare, heterogenous group of diseases characterized by extracellular infiltration and deposition of amyloid fibrils. Cardiac amyloidosis (CA) occurs when these fibrils deposit within the myocardium. Untreated, this inevitably leads to progressive heart failure and fatality. Historically, treatment has remained supportive, however, there are now targeted disease-modifying therapeutics available to patients with CA. Advances in echocardiography, cardiac magnetic resonance (CMR) and repurposed bone scintigraphy have led to a surge in diagnoses of CA and diagnosis at an earlier stage of the disease natural history. CMR has inherent advantages in tissue characterization which has allowed us to better understand the pathological disease process behind CA. Combined with specialist assessment and repurposed bone scintigraphy, diagnosis of CA can be made without the need for invasive histology in a significant proportion of patients. With existing targeted therapeutics, and novel agents being developed, understanding these imaging modalities is crucial to achieving early diagnosis for patients with CA. This will allow for early treatment intervention, accurate monitoring of disease course over time, and thereby improve the length and quality of life of patients with a disease that historically had an extremely poor prognosis. In this review, we discuss key radiological features of CA, focusing on the two most common types; immunoglobulin light chain (AL) and transthyretin (ATTR) CA. We highlight recent advances in imaging techniques particularly in respect of their clinical application and utility in diagnosis of CA as well as for tracking disease change over time.

scholarly journals Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 11 ◽  
Author(s):  
Haruki Koike ◽  
Masahisa Katsuno
Keyword(s):  
Elderly Population ◽  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Therapeutic Option ◽  
The Elderly ◽  
Organ Damage ◽  
Phase Iii ◽  
Wild Type ◽  
Electron Microscopic ◽  
Transthyretin Amyloidosis

Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.

scholarly journals Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

2017 ◽  
Vol 11 ◽  
pp. 117954681773032 ◽  
Author(s):  
Marla B Sultan ◽  
Balarama Gundapaneni ◽  
Jennifer Schumacher ◽  
Jeffrey H Schwartz
Keyword(s):  
Disease Progression ◽  
Amyloid Fibrils ◽  
Early Stage ◽  
Heart Association ◽  
Analysis Data ◽  
Amyloid Formation ◽  
Functional Classification ◽  
Wild Type ◽  
Open Label ◽  
Transthyretin Amyloidosis

Background: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation. Methods: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. Results: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients ( P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification ( P = .0262). Conclusions: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. Trial Registration: ClinicalTrials.gov, NCT00694161.

scholarly journals Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases

2010 ◽  
Vol 12 ◽  
Author(s):  
Jacques Fantini ◽  
Nouara Yahi
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Fine Tuning ◽  
Neural Cells ◽  
Amyloidogenic Proteins ◽  
Innovative Therapies ◽  
Conformational Plasticity ◽  
Direct Binding ◽  
Α Helix

Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.

Exploring the structure and formation mechanism of amyloid fibrils by Raman spectroscopy: a review

The Analyst ◽  
2015 ◽  
Vol 140 (15) ◽  
pp. 4967-4980 ◽  
Author(s):  
Dmitry Kurouski ◽  
Richard P. Van Duyne ◽  
Igor K. Lednev
Keyword(s):  
Raman Spectroscopy ◽  
Formation Mechanism ◽  
Structural Characterization ◽  
Amyloid Fibrils ◽  
Label Free ◽  
Amyloidogenic Proteins ◽  
Non Destructive

Applications of Raman spectroscopy, a label-free non-destructive technique, for the structural characterization of amyloidogenic proteins, prefibrilar oligomers, and mature fibrils.

scholarly journals Structure of an infectious mammalian prion

2021 ◽  
Author(s):  
Allison Kraus ◽  
Forrest Hoyt ◽  
Cindi L. Schwartz ◽  
Bryan Hansen ◽  
Andrew G. Hughson ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Prion Proteins ◽  
Beta Sheets ◽  
Infectious Agents ◽  
Biophysical Properties ◽  
Amyloidogenic Proteins ◽  
Cryo Electron Microscopy ◽  
Polypeptide Backbone ◽  
Mammalian Prions ◽  
Lethal Doses

ABSTRACTClassical mammalian prions are assemblies of prion protein molecules that are extraordinarily transmissible, with a microgram of protein containing up to 108 lethal doses of infectivity1,2. Unlike most other pathologic and amyloidogenic proteins, prions typically contain glycolipid anchors 3 and abundant asparagine‐linked glycans4‐6. The infectious nature, complexity, and biophysical properties of prions have complicated structural analyses and stymied any prior elucidation of 3D conformation at the polypeptide backbone level7. Here we have determined the structure of the core of a fully infectious, brain‐derived prion by cryo‐electron microscopy with ∼3.1 Å resolution. The purified prions are amyloid fibrils comprised of monomers assembled with parallel in‐register intermolecular beta sheets and connecting chains. Residues ∼95‐227 of each monomer provide one rung of the ordered fibril core, with the glycans and glycolipid anchor projecting from the lateral surfaces of the fibril. The fibril ends, where prion growth occurs, are formed by single monomers in an extended serpentine combination of β‐ arches, a Greek key, and loops that presumably template the refolding of incoming monomers. Our results describe an atomic model to underpin detailed molecular hypotheses of how pathologic prion proteins can propagate as infectious agents, and how such propagation and associated pathogenesis might be impeded.

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