International Journal of Molecular Sciences

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3 pages, 180 KiB

Open AccessEditorial

Molecular Research on Amyloidosis

by Kazufumi Nakamura

Int. J. Mol. Sci. 2023, 24(8), 6980; https://doi.org/10.3390/ijms24086980 - 10 Apr 2023

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Abstract

Amyloidosis is a large group of diseases that are caused by the deposition of insoluble amyloid fibrils formed by misfolded soluble proteins in organs or tissues [...] Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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11 pages, 2836 KiB

Open AccessArticle

Microcalcification and ^99mTc-Pyrophosphate Uptake without Increased Bone Metabolism in Cardiac Tissue from Patients with Transthyretin Cardiac Amyloidosis

by Atsushi Mori, Yukihiro Saito, Kazufumi Nakamura, Toshihiro Iida, Satoshi Akagi, Masashi Yoshida, Makiko Taniyama, Toru Miyoshi and Hiroshi Ito

Int. J. Mol. Sci. 2023, 24(3), 1921; https://doi.org/10.3390/ijms24031921 - 18 Jan 2023

Cited by 3 | Viewed by 2094

Abstract

Transthyretin cardiac amyloidosis (ATTR-CA) is characterized by high ^99mTc-labeled bone tracer uptake in the heart. However, the mechanism of bone tracer uptake into the heart remains controversial. Since bone tracer uptake into metastatic bone tumors is thought to be associated with increased [...] Read more.

Transthyretin cardiac amyloidosis (ATTR-CA) is characterized by high ^99mTc-labeled bone tracer uptake in the heart. However, the mechanism of bone tracer uptake into the heart remains controversial. Since bone tracer uptake into metastatic bone tumors is thought to be associated with increased bone metabolism, we examined ^99mTc-pyrophosphate (PYP) scintigraphy findings, endomyocardial biopsy (EMB) tissue findings, and the expression of bone metabolism-related genes in the EMB tissues in patients with ATTR-CA, amyloid light-chain cardiac amyloidosis (AL-CA), and noncardiac amyloidosis (non-CA) in this study. The uptake of ^99mTc-PYP in the heart was significantly higher in the ATTR-CA patients than in the AL-CA and non-CA patients. A higher percentage of ATTR-CA EMB tissue showed von Kossa-positive microparticles: ATTR-CA, 62%; AL-CA, 33%; and non-CA, 0%. Calcified microparticles were identified using transmission electron microscopy. However, none of the osteogenic marker genes, osteoclastic marker genes, or phosphate/pyrophosphate-related genes were upregulated in the EMB samples from ATTR-CA patients compared to those from AL-CA and non-CA patients. These results suggest that active calcification-promoting mechanisms are not involved in the microcalcification observed in the heart in ATTR-CA. The mechanisms explaining bone tracer uptake in the heart, which is stronger than that in the ribs, require further investigation. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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18 pages, 2908 KiB

Open AccessArticle

The Apparent Organ-Specificity of Amyloidogenic ApoA-I Variants Is Linked to Tissue-Specific Extracellular Matrix Components

by Rita Del Giudice, Mikaela Lindvall, Oktawia Nilsson, Daria Maria Monti and Jens O. Lagerstedt

Int. J. Mol. Sci. 2023, 24(1), 318; https://doi.org/10.3390/ijms24010318 - 24 Dec 2022

Cited by 3 | Viewed by 1788

Abstract

Apolipoprotein A-I (ApoA-I) amyloidosis is a rare protein misfolding disease where fibrils of the N-terminal domain of the protein accumulate in several organs, leading to their failure. Although ApoA-I amyloidosis is systemic, the different amyloidogenic variants show a preferential tissue accumulation that appears [...] Read more.

Apolipoprotein A-I (ApoA-I) amyloidosis is a rare protein misfolding disease where fibrils of the N-terminal domain of the protein accumulate in several organs, leading to their failure. Although ApoA-I amyloidosis is systemic, the different amyloidogenic variants show a preferential tissue accumulation that appears to correlate with the location of the mutation in the protein sequence and with the local extracellular microenvironment. However, the factors leading to cell/tissues damage, as well as the mechanisms behind the observed organ specificity are mostly unknown. Therefore, we investigated the impact of ApoA-I variants on cell physiology and the mechanisms driving the observed tissue specificity. We focused on four ApoA-I amyloidogenic variants and analyzed their cytotoxicity as well as their ability to alter redox homeostasis in cell lines from different tissues (liver, kidney, heart, skin). Moreover, variant-specific interactions with extracellular matrix (ECM) components were measured by synchrotron radiation circular dichroism and enzyme-linked immunosorbent assay. Data indicated that ApoA-I variants exerted a cytotoxic effect in a time and cell-type-specific manner that seems to be due to protein accumulation in lysosomes. Interestingly, the ApoA-I variants exhibited specific preferential binding to the ECM components, reflecting their tissue accumulation pattern in vivo. While the binding did not to appear to affect protein conformations in solution, extended incubation of the amyloidogenic variants in the presence of different ECM components resulted in different aggregation propensity and aggregation patterns. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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14 pages, 2725 KiB

Open AccessArticle

Autophagy Alteration in ApoA-I Related Systemic Amyloidosis

by Rita Del Giudice, Paola Imbimbo, Federico Pietrocola, Isabelle Martins, Fatima Domenica Elisa De Palma, José Manuel Bravo-San Pedro, Guido Kroemer, Maria Chiara Maiuri and Daria Maria Monti

Int. J. Mol. Sci. 2022, 23(7), 3498; https://doi.org/10.3390/ijms23073498 - 23 Mar 2022

Cited by 4 | Viewed by 2453

Abstract

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset [...] Read more.

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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12 pages, 1458 KiB

Open AccessReview

Diagnostic Challenges and Solutions in Systemic Amyloidosis

by Rivka Goldis, Batia Kaplan, Olga (Lesya) Kukuy, Michael Arad, Hila Magen, Efrat Shavit-Stein, Amir Dori and Avi Livneh

Int. J. Mol. Sci. 2023, 24(5), 4655; https://doi.org/10.3390/ijms24054655 - 28 Feb 2023

Cited by 4 | Viewed by 2542

Abstract

Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of [...] Read more.

Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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22 pages, 767 KiB

Open AccessReview

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

by Mario Nuvolone, Maria Girelli and Giampaolo Merlini

Int. J. Mol. Sci. 2022, 23(24), 16145; https://doi.org/10.3390/ijms232416145 - 18 Dec 2022

Cited by 3 | Viewed by 4879

Abstract

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain [...] Read more.

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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15 pages, 1125 KiB

Open AccessReview

Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

by Hidehiko Ikura, Jin Endo, Hiroki Kitakata, Hidenori Moriyama, Motoaki Sano and Keiichi Fukuda

Int. J. Mol. Sci. 2022, 23(11), 6336; https://doi.org/10.3390/ijms23116336 - 6 Jun 2022

Cited by 9 | Viewed by 8831

Abstract

In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. AL [...] Read more.

In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. AL amyloidosis progresses much faster than other types of amyloidosis, with a slight delay in diagnosis leading to a marked exacerbation of cardiomyopathy. In some cases, the resulting heart failure is so severe that chemotherapy cannot be administered, and death sometimes occurs within a few months. To date, many clinical studies have focused on therapeutics, especially chemotherapy, to treat this disease. Because it is necessary to promptly lower FLC, the causative protein of amyloid, to achieve a hematological response, various anticancer agents targeting neoplastic plasma cells are used for the treatment of this disease. In addition, many basic studies using human specimens to elucidate the pathophysiology of AL have been conducted. Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. This review outlines the pathogenesis and treatment strategies for AL amyloidosis with respect to its molecular mechanisms. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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16 pages, 553 KiB

Open AccessReview

Molecular Mechanisms of Cardiac Amyloidosis

by Yukihiro Saito, Kazufumi Nakamura and Hiroshi Ito

Int. J. Mol. Sci. 2022, 23(1), 25; https://doi.org/10.3390/ijms23010025 - 21 Dec 2021

Cited by 30 | Viewed by 4095

Abstract

Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, [...] Read more.

Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis. Full article

(This article belongs to the Special Issue Molecular Research on Amyloidosis)

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