Systemic amyloidoses.
Ontology highlight
ABSTRACT:
SUBMITTER: Blancas-Mejia LM
PROVIDER: S-EPMC4044913 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses. These include both localized (e.g. Alzheimer's disease, prion diseases, type 2 diabetes mellitus) and systemic amyloidoses. Historically regarded as a group of maladies with limited, even inexistent, therapeutic options, some forms of systemic amyloidoses have recently witnessed a series of unparalleled therapeutic successes, positively impacting on their natural history and sometimes even on their incidence. In this review article we will revisit the most relevant of these accomplishments. Collectively, current evidence converges towards a crucial role of an early and conspicuous reduction or stabilization of the amyloid-forming protein in its native conformation. Such an approach can reduce disease incidence in at risk individuals, limit organ function deterioration, promote organ function recovery, improve quality of life and extend survival in diseased subjects. Therapeutic success achieved in these forms of systemic amyloidoses may guide the research on other protein misfolding and deposition diseases for which effective etiologic therapeutic options are still absent.
| S-EPMC7366848 | biostudies-literature
Project description:In the human systemic amyloidoses caused by mutant or wild-type transthyretin (TTR), deposition occurs at a distance from the site of synthesis. The TTR synthesized and secreted by the hepatocyte circulates in plasma, then deposits in target tissues far from the producing cell, a pattern reproduced in mice transgenic for multiple copies of the human wild-type TTR gene. By 2 yr of age, half of the transgenic males show cardiac deposition resembling human senile systemic amyloidosis. However, as early as 3 mo of age, when there are no deposits, cardiac gene transcription differs from that of nontransgenic littermates, primarily in the expression of a large number of genes associated with inflammation and the immune response. At 24 mo, the hearts with histologically proven TTR deposits show expression of stress response genes, exuberant mitochondrial gene transcription, and increased expression of genes associated with apoptosis, relative to the hearts without TTR deposition. These 24-mo-old hearts with TTR deposits also show a decrease in transcription of inflammatory genes relative to that in the younger transgenic mice. After 2 yr of expressing large amounts of human TTR, the livers of the transgenic mice without cardiac deposition display chaperone gene expression and evidence of an activated unfolded protein response, while the livers of animals with cardiac TTR deposition display neither, showing increased transcription of interferon-responsive inflammatory genes and those encoding an antioxidant response. With time, in animals with cardiac deposition, it appears that hepatic proteostatic capacity is diminished, exposing the heart to a greater load of misfolded TTR with subsequent extracellular deposition. Hence systemic (cardiac) TTR deposition may be the direct result of the diminution in the distant chaperoning capacity of the liver related to age or long-standing exposure to misfolded TTR, or both.
| S-EPMC3360152 | biostudies-other
Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann-Sträussler-Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.
| S-EPMC8270882 | biostudies-literature
Project description:Small molecules that bind to normally unoccupied thyroxine (T(4)) binding sites within transthyretin (TTR) in the blood stabilize the tetrameric ground state of TTR relative to the dissociative transition state and dramatically slow tetramer dissociation, the rate-limiting step for the process of amyloid fibril formation linked to neurodegeneration and cell death. These so-called TTR kinetic stabilizers have been designed using structure-based principles and one of these has recently been shown to halt the progression of a human TTR amyloid disease in a clinical trial, providing the first pharmacologic evidence that the process of amyloid fibril formation is causative. Structure-based design has now progressed to the point where highly selective, high affinity TTR kinetic stabilizers that lack undesirable off-target activities can be produced with high frequency.
| S-EPMC2830738 | biostudies-literature
Project description:Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson's disease and Huntington's disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson's disease, Huntington's disease, Alzheimer's disease, and other amyloidoses.
| S-EPMC5100551 | biostudies-literature
Project description:Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26-57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26-57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility.
| S-EPMC4192486 | biostudies-literature
Project description:Type 2 diabetes (T2D) and Alzheimer's disease (AD) represent two most prevalent amyloid diseases with a significant global burden. Pathologically, T2D and AD are characterized by the presence of amyloid plaques consisting primarily of toxic human islet amyloid polypeptide (IAPP) and amyloid beta (Aβ). It has been recently revealed that the gut microbiome plays key functions in the pathological progression of neurological disorders through the production of bacterial endotoxins, such as lipopolysaccharide (LPS). In this study, we examined the catalytic effects of LPS on IAPP and Aβ amyloidoses, and further demonstrated their mitigation with zero-dimensional carbon quantum dots (CQDs). Whereas LPS displayed preferred binding with the N-terminus of IAPP and the central hydrophobic core and C-terminus of Aβ, CQDs exhibited propensities for the amyloidogenic and C-terminus regions of IAPP and the N-terminus of Aβ, accordingly. The inhibitory effect of CQDs was verified by an embryonic zebrafish model exposed to the peptides and LPS, where impaired embryonic hatching was rescued and production of reactive oxygen species in the organism was suppressed by the nanomaterial. This study revealed a robust synergy between LPS and amyloid peptides in toxicity induction, and implicated CQDs as a potential therapeutic against the pathologies of T2D and AD.
| S-EPMC7325865 | biostudies-literature
Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.
2022-02-17 | PXD025663 | Pride
Project description:It is well established that the formation of transthyretin (TTR) amyloid fibrils is linked to the destabilization and dissociation of its tetrameric structure into insoluble aggregates. Isotope labeling is used for the study of TTR by NMR, neutron diffraction, and mass spectrometry (MS). Here MS, thioflavin T fluorescence, and crystallographic data demonstrate that while the X-ray structures of unlabeled and deuterium-labeled TTR are essentially identical, subunit exchange kinetics and amyloid formation are accelerated for the deuterated protein. However, a slower subunit exchange is noted in deuterated solvent, reflecting the poorer solubility of non-polar protein side chains in such an environment. These observations are important for the interpretation of kinetic studies involving deuteration. The destabilizing effects of TTR deuteration are rather similar in character to those observed for aggressive mutations of TTR such as L55P (associated with familial amyloid polyneuropathy).
| S-EPMC5094506 | biostudies-literature
Project description:The transthyretin (TTR) amyloidoses are human diseases in which the misfolded TTR protein aggregates in tissues with subsequent visceral, peripheral, and autonomic nerve dysfunction. Recent reports have stressed the importance of oligomeric intermediates as major cytotoxic species in various forms of amyloidogenesis. We have examined the cytotoxic effects of several quaternary structural states of wild-type and variant TTR proteins on cells of neural lineage. TTR amyloid fibrils and soluble aggregates >100 kDa were not toxic. Incubation of TTR under the conditions of the cell assay and analysis by size-exclusion chromatography and SDS/PAGE reveal that monomeric TTR or relatively small, rapidly formed aggregates of a maximum size of six subunits were the major cytotoxic species. Small molecules that stabilize the native tetrameric state were shown to prevent toxicity. The studies are consistent with a model in which the misfolded TTR monomer rapidly aggregates to form transient low molecular mass assemblies (<100 kDa) that are highly cytotoxic in tissue culture.
| S-EPMC365703 | biostudies-literature