Systemic amyloidosis derived from EFEMP1 in a captive Tsushima leopard cat

2021 ◽  
pp. 030098582110486
Author(s):  
Shinya Miyazaki ◽  
Yuki Kobayashi ◽  
Fuyuki Kametani ◽  
Kyoko Kobayashi ◽  
Susumu Iwaide ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Systemic Amyloidosis ◽  
Extracellular Matrix Protein ◽  
Amyloid A ◽  
Multiple Organs ◽  
Age Related ◽  
Amyloid Deposits ◽  
Amyloidogenic Region ◽  
Leopard Cat ◽  
Different Characteristics

In animals, most cases of systemic amyloidosis are of amyloid A type, and the other types of systemic amyloidoses are rare. This study analyzed systemic amyloidosis in a 15-year-old female Tsushima leopard cat. Amyloid deposits strongly positive for Congo red staining were observed in the arterial walls as well as the interstitium in multiple organs. Mass spectrometry–based proteomic analysis with laser microdissection of amyloid deposits identified epidermal growth factor–containing fibulin-like extracellular matrix protein 1 (EFEMP1) as a prime amyloidogenic protein candidate. Immunohistochemistry showed that the amyloid deposits were positive for the N-terminal region of EFEMP1. From these results, the present case was diagnosed as EFEMP1-derived amyloidosis. It is the first such case in an animal. EFEMP1-derived amyloidosis in humans has recently been reported as a systemic amyloidosis, and it is known as an age-related venous amyloidosis. The present case showed different characteristics from human EFEMP1-derived amyloidosis, including the amyloid deposition sites and the amyloidogenic region of the EFEMP1 protein, suggesting a different pathogenesis between Tsushima leopard cat and human EFEMP1-derived amyloidosis.

scholarly journals Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
DaNae R. Woodard ◽  
Emi Nakahara ◽  
John D. Hulleman
Keyword(s):  
Matrix Protein ◽  
Cultured Cells ◽  
Open Angle Glaucoma ◽  
Culture Conditions ◽  
Glycosylation Site ◽  
Age Related Macular Degeneration ◽  
Extracellular Matrix Protein ◽  
Macular Dystrophy ◽  
Alternative Mechanism ◽  
Age Related

AbstractDistinct mutations in the secreted extracellular matrix protein, fibulin-3 (F3), have been associated with a number of ocular diseases ranging from primary open angle glaucoma to cuticular age-related macular degeneration to a rare macular dystrophy, Malattia Leventinese (ML). The R345W F3 mutation that causes ML leads to F3 misfolding, inefficient secretion and accumulation at higher intracellular steady state levels in cultured cells. Herein, we determined whether fifteen other clinically-identified F3 mutations also led to similar levels of misfolding and secretion defects, which might provide insight into their potential pathogenicity. Surprisingly, we found that only a single F3 variant, L451F, presented with a significant secretion defect (69.5 ± 2.4% of wild-type (WT) F3 levels) and a corresponding increase in intracellular levels (226.8 ± 25.4% of WT F3 levels). Upon follow-up studies, when this conserved residue (L451) was mutated to a charged (Asp or Arg) or bulky (Pro, Trp, Tyr) residue, F3 secretion was also compromised, indicating the importance of small side chains (Leu, Ala, or Gly) at this residue. To uncover potential inherent F3 instability not easily observed under typical culture conditions, we genetically eliminated the sole stabilizing N-linked glycosylation site (N249) from select clinically-identified F3 mutants. This removal exacerbated R345W and L451F secretion defects (19.8 ± 3.0% and 12.4 ± 1.2% of WT F3 levels, respectively), but also revealed a previously undiscovered secretion defect in another C-terminal variant, Y397H (42.0 ± 10.1% of WT F3 levels). Yet, glycan removal did not change the relative secretion of the N-terminal mutants tested (D49A, R140W, I220F). These results highlight the uniqueness and molecular similarities between the R345W and L451F variants and also suggest that previously identified disease-associated mutations (e.g., R140W) are indistinguishable from WT with respect to secretion, hinting that they may lead to disease by an alternative mechanism.

Abstract P139: Genetic Signature Of Accelerated Cardiac Fibrosis Due To Trpa1 Ablation

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Shuangtao Ma ◽  
Donna Wang
Keyword(s):  
Matrix Metalloproteinases ◽  
Matrix Protein ◽  
Cardiac Fibrosis ◽  
Collagen Fibers ◽  
Extracellular Matrix Protein ◽  
Myocardial Tissue ◽  
Mrna Levels ◽  
Wild Type ◽  
Genetic Signature ◽  
Age Related

While our previous study demonstrated that loss of transient receptor potential ankyrin 1 ( Trpa1 ) accelerates age-related cardiac fibrosis in mice, the underlying mechanism of potential anti-fibrotic property of TRPA1 remains largely unknown. TRPA1 is a sensor of oxidative stress and may play a protective role in age-related diseases. In this study, we performed quantitative polymerase chain reaction array analyses of the mRNA expression of 84 fibrosis-related genes in the myocardial tissue of 12-month-old Trpa1 -/- mice with significant cardiac fibrosis and age-matched wild-type mice without cardiac fibrosis. The mRNA levels of Col1a2 and Col3a1 in the myocardial tissue were similar between Trpa1 -/- and wild-type mice, suggesting comparable cardiac collagen synthesis in the two strains. Matrix metalloproteinases are major enzymes responsible for degradation of collagen fibers. The results show that the mRNA levels of matrix metalloproteinases, including Mmp1a , Mmp2 , Mmp3 , Mmp8 , Mmp9 , Mmp13 , and Mmp14 , in the heart were similar between Trpa1 -/- and wild-type mice. Nevertheless, we identified 7 significantly changed genes in the heart between the two strains. The expression levels of Acta2 , Inhbe , Ifng , and Ccl11 were significantly increased with fold changes of 3.1, 1.9, 1.9, and 1.5 (all P < 0.05), respectively, while Timp3 , Stat6 , and Ilk were significantly decreased with fold changes of 0.3, 0.5, and 0.7 (all P < 0.05), respectively, in the heart of Trpa1 -/- mice compared with wild-type mice. Acta2 , the most upregulated gene in Trpa1 -/- hearts, is a marker of myofibroblasts. Its upregulation indicates increased differentiation from fibroblasts into myofibroblasts in Trpa1 -/- hearts compared with wild-type hearts. Timp3 , the most downregulated gene in Trpa1 -/- hearts, codes an extracellular matrix protein TIMP3, which not only inhibits matrix metalloproteinases but also regulate post-translational modification of collagen fibers. Taken together, these findings suggest that upregulation of Acta2 and downregulation of Timp3 may serve as genetic signature or play a role in accelerated age-related cardiac fibrosis due to TRPA1 ablation.

A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1

2018 ◽  
Vol 247 (4) ◽  
pp. 444-455 ◽  
Author(s):  
Masayoshi Tasaki ◽  
Mitsuharu Ueda ◽  
Yoshinobu Hoshii ◽  
Mayumi Mizukami ◽  
Sayaka Matsumoto ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Extracellular Matrix Protein 1 ◽  
Age Related

scholarly journals Colocalization of Apolipoprotein AI in Various Kinds of Systemic Amyloidosis

2005 ◽  
Vol 53 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Naohiro Sakata ◽  
Yoshinobu Hoshii ◽  
Tomomi Nakamura ◽  
Makiko Kiyama ◽  
Hirofumi Arai ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Systemic Amyloidosis ◽  
High Density Lipoproteins ◽  
Apolipoprotein Ai ◽  
Aa Amyloidosis ◽  
Amyloid A ◽  
Amyloid Deposits ◽  
A Minor

Apolipoprotein AI (apoAI), a major component of high-density lipoproteins, is one of the major amyloid fibril proteins and a minor constituent of the senile plaques observed in Alzheimer's disease. We examined colocalization of apoAI in various kinds of systemic amyloidosis in this study. Forty-three of 48 formalin-fixed paraffin-embedded heart specimens with various forms of systemic amyloidosis reacted immunohistochemically with anti-human apoAI antibody. ApoAI was also detected in water-extracted amyloid material by immunoblotting. In addition, we observed colocalization of apoAI and murine amyloid A (AA) amyloidosis in human apoAI transgenic mice. This is the first report of colocalization of apoAI with amyloid deposits in various forms of human systemic amyloidosis and murine AA amyloidosis in human apoAI transgenic mice. ApoAI may not always be a major component of amyloid fibrils, even when it is present in systemic amyloid deposits.

scholarly journals Functional Expression of Mouse Relaxin and Mouse Relaxin-3 in the Lung from an Ebola Virus Glycoprotein-Pseudotyped Lentivirus via Tracheal Delivery

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3797-3808 ◽  
Author(s):  
Josh D. Silvertown ◽  
Jagdeep S. Walia ◽  
Alastair J. Summerlee ◽  
Jeffrey A. Medin
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Peptide Hormone ◽  
Biologically Active ◽  
Extracellular Matrix Protein ◽  
Mouse Lung ◽  
Protein Accumulation ◽  
Virus Glycoprotein ◽  
Age Related

The peptide hormone relaxin is a known modulator of connective tissue and the extracellular matrix by virtue of its ability to regulate matrix metalloproteinases (MMPs). Relaxin knockout mice exhibit age-related pulmonary fibrosis, and delivery of recombinant human H2 relaxin ameliorates fibrotic-like conditions in the mouse lung. We investigated whether lentiviral vectors (LVs) engineering the expression of murine relaxins could induce MMP activity in the mouse lung. Mouse relaxin and mouse relaxin-3 peptides engineered by recombinant LVs were biologically active as shown by stimulation of cAMP from both THP-1 and 293T cells stably expressing relaxin receptor LGR7 and by up-regulation of MMP-2 activity from primary C57BL/6 lung cell cultures. To provide the virions with enhanced tropism for the lung, LVs were pseudotyped with the Zaire strain of the Ebola virus glycoprotein (EboZ GP) and delivered by endotracheal intubation. LVs engineering luciferase pseudotyped with EboZ GP, but not with vesicular stomatitis virus glycoprotein resulted in successful LV transduction and transgene expression in C57BL/6 mouse lung by as early as d 4. Mice treated via tracheal delivery with EboZ GP pseudotyped LVs that engineered expression of mouse relaxins exhibited increased MMP-2 and MMP-9 activity in lung tissue up until the end of our study at d 21. Taken together, this study provides proof-of- principle that relaxin gene expression targeted to the mouse lungs can result in enhanced MMP activity offering potential for alleviating disease conditions characterized by dysregulation of extracellular matrix protein accumulation.

scholarly journals Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

2019 ◽  
Author(s):  
Olga Katsara ◽  
Mukundan Attur ◽  
Victoria Kolupaeva
Keyword(s):  
Translational Control ◽  
Matrix Protein ◽  
Cartilage Degeneration ◽  
Joint Disease ◽  
Extracellular Matrix Protein ◽  
World Population ◽  
Orphan Nuclear Receptor ◽  
Age Related ◽  
Osteoarthritis Progression ◽  
Articular Cartilage Degeneration

ABSTRACTAs world population growing older, burden of age-related conditions soars. One of them is osteoarthritis (OA), a debilitating joint disease with no effective treatment. Articular cartilage degeneration is a central event in OA, and changes in expression of many genes in OA cartilage are well-documented. Still, the specific mechanisms are rarely known. We showed that in OA cartilage the increased abundance of many proteins, including extracellular matrix protein Fibronectin (Fn1) and an orphan nuclear receptor Nr4a1 is translationally controlled and requires inactivation of 4EBP, an inhibitor of cap-dependent translation. Importantly, intra-articular injection of the translation inhibitor 4E1RCat reduces Fn1 and Nr4a upregulation in a rodent OA model and delays cartilage degeneration. Our results support the hypothesis that maintaining proper translational control is an important homeostatic mechanism, the loss of which contributes to OA development.

scholarly journals Extracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huijing Yin ◽  
Jingshu Wang ◽  
Hui Li ◽  
Yinjue Yu ◽  
Xiaoling Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Mrna Splicing ◽  
Extracellular Matrix Protein ◽  
Good Survival ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Multiple Organs ◽  
Extracellular Matrix Protein 1 ◽  
Alternative Mrna Splicing ◽  
Nuclear Ribonucleoprotein

AbstractExtracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.

PARALLEL CHANGES IN EXTRACELLULAR MATRIX PROTEIN GENE EXPRESSION, BONE FORMATION AND BIOMECHANICAL PROPERTIES IN AGING RAT BONE

2002 ◽  
Vol 06 (03n04) ◽  
pp. 157-169 ◽  
Author(s):  
Kathleen M. Buhl ◽  
Christopher R. Jacobs ◽  
Russell T. Turner ◽  
Glenda L. Evans ◽  
Peter A. Farrell ◽  
...  
Keyword(s):  
Bone Formation ◽  
Mrna Expression ◽  
Cancellous Bone ◽  
Material Properties ◽  
Matrix Protein ◽  
Bone Geometry ◽  
Extracellular Matrix Protein ◽  
Type I ◽  
Bone Formation Rate ◽  
Age Related

The effect of aging on long bone mechanical properties and bone formative capacity was characterized in the male Fisher 344 rat. The femurs of rats from three age groups (4 mo., 12 mo. and 28 mo.) were tested in three-point bending to determine their structural properties. The apparent material properties were then calculated by adjusting for bone geometry. Bone formation was assessed by dynamic histomorphometry of both cortical and cancellous bone as well as by Northern blot analysis for the expression of the osteoblast phenotypic proteins osteopontin (OP), osteocalcin (OC), type I collagen (COL) and alkaline phosphatase (AP). Aging resulted in a decline in the apparent material properties that was associated with a compensatory alteration of bone geometry that preserved structural strength and stiffness. Histomorphometric analysis revealed significant age-related decreases in cancellous bone volume, trabecular number and increased trabecular separation suggesting the existence of senile osteopenia in the proximal tibia of the male Fisher 344 rat. A significant decline in bone formation rate (BFR), but not mineral apposition rate, suggests that a reduction in osteoblast number, but not osteoblast activity, contributes to age-related bone loss. The decline in BFR with aging was reflected in a decreased mRNA expression for OP, OC and COL but not AP. Further, the pattern of mRNA expression was consistent with reduced osteoblast differentiation with aging. The present study indicates the age-related decline in material properties of long bones is paralleled by a decrease in osteogenesis.

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