Structure-Based Probe Reveals the Presence of Large Transthyretin Aggregates in Plasma of ATTR Amyloidosis Patients.

Amyloidogenic transthyretin (ATTR) amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic transthyretin into amyloid fibrils. These fibrils cause diverse clinical phenotypes, mainly cardiomyopathy and/or polyneuropathy. Little is known about the aggregation of transthyretin during disease development and whether this has implications for diagnosis and treatment.

ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity.

Amyloidogenic transthyretin (ATTR) amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin. Transthyretin is primarily produced in tetrameric form by the liver, but also by retinal epithelium and choroid plexus. The deposition of these fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant.

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable.

O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.

Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease.

Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy.

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils.

O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology.

The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer's and Parkinson's disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies.

Update on Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis.

Purpose Of Review: Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy and an increasingly recognized cause of morbidity and mortality. There remains substantial delay between initial symptoms and diagnosis. With the recent emergence of various targeted therapies proven to reduce morbidity and mortality, there is an imperative to diagnose subclinical disease.