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| ==Pathophysiology== | | ==Pathophysiology== |
| ===Pathogenesis=== | | ===Pathogenesis=== |
| '''Amyloids'''
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| *Amyloids consist of aggregated proteins that accumulate extracellularly as insoluble fibrils of misfolded proteins. Pathogenic amyloids are the consequence of previously normal proteins that lose their physiological properties and assume a beta-pleated quaternary configuration with a characteristic appearance on electron microscopy. The axis of the fiber (5-15nm in width) in these deposits is perpendicular to antiparallel chains of beta peptides. | | * Wild-type (senile) amyloidosis is a type of systemic amyloidosis. |
| | | * The culprit protein responsible for the disease is transthyretin (TTR) and it is deposited in the non-mutated form, hence the name "Wild-type". |
| *These misfolded proteins are seen in various diseases such as Alzheimer's disease (beta-amyloid), diabetes mellitus type 2 (amylin), Parkinson's disease (alpha-synuclein), fatal familial insomnia (PrPsc), Huntington's disease (Huntingtin), medullary carcinoma of the thyroid (calcitonin), atherosclerosis (apolipiprotein A-I), rheumatoid arthritis (serm amyloid A), Lattice corneal dystrophy (keratoepithelin) and trasnmissible spongiform encephalopathy (PrP). | | * The normal TTR protein compared with the mutated form is less likely to get deposited and to cause a pathology |
| *Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers.
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| '''Interaction of Amyloid Fibrils with Microenvironment'''
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| *Accumulation of insoluble amyloid fibrils in tissues leads to activation proteosomes that lead to their endoproteolysis and release of amyloidogenic light chain fragments.
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| *Interaction of these deposits with extracellular chaperones, matrix components including glycosaminoglycans (GAGs) and collagen, shear forces, endoproteases, and metals modulate aggregation and oligomer formation.
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| '''Tissue damage'''
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| *The deposition of amyloid aggregates leads to architectural disruptions in tissues.
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| *Amyloid fibrils may also produce organ dysfunction via interaction with ligands and disruption of cell membranes.
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| *Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.<ref name="RiekEisenberg2016">{{cite journal|last1=Riek|first1=Roland|last2=Eisenberg|first2=David S.|title=The activities of amyloids from a structural perspective|journal=Nature|volume=539|issue=7628|year=2016|pages=227–235|issn=0028-0836|doi=10.1038/nature20416}}</ref>
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| *Specificity for a particular organ in primary amyloidosis depends upon the light chain variable region gene and gene family of the clone. Germ line gene LV6-57 is more common in AL systemic amyloidosis and is associated with renal involvement, while LV1-44 preferentially leads to fibril deposition in the heart and KV1-33 is associated with hepatic involvement.<ref name="pmid22067386">{{cite journal |vauthors=Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy C, Merlini G |title=The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44 |journal=Blood |volume=119 |issue=1 |pages=144–50 |date=January 2012 |pmid=22067386 |doi=10.1182/blood-2011-05-355784 |url=}}</ref> | |
| *It has also been shown that cardiac fibroblasts internalize amyloid deposits which then migrate to mitochondrial optic atrophy 1-like protein and peroxisomal acyl-coenzyme A oxidase 1 leading to toxicity.<ref name="pmid26220173">{{cite journal |vauthors=Lavatelli F, Imperlini E, Orrù S, Rognoni P, Sarnataro D, Palladini G, Malpasso G, Soriano ME, Di Fonzo A, Valentini V, Gnecchi M, Perlini S, Salvatore F, Merlini G |title=Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis |journal=FASEB J. |volume=29 |issue=11 |pages=4614–28 |date=November 2015 |pmid=26220173 |doi=10.1096/fj.15-272179 |url=}}</ref>
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| ==References== | | ==References== |