Wild-type (senile) amyloidosis pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
'''Amyloids''' | '''Amyloids''' | ||
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*Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers. | *Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers. | ||
'''Interaction of Amyloid | '''Interaction of Amyloid Fibrils with Microenvironment''' | ||
*Accumulation of insoluble amyloid fibrils in tissues leads to activation proteosomes that lead to their endoproteolysis and release of amyloidogenic light chain fragments. | *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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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]
Overview
Pathophysiology
Pathogenesis
Amyloids
- 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.
- 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).
- Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers.
Interaction of Amyloid Fibrils with Microenvironment
- Accumulation of insoluble amyloid fibrils in tissues leads to activation proteosomes that lead to their endoproteolysis and release of amyloidogenic light chain fragments.
- Interaction of these deposits with extracellular chaperones, matrix components including glycosaminoglycans (GAGs) and collagen, shear forces, endoproteases, and metals modulate aggregation and oligomer formation.
Tissue damage
- The deposition of amyloid aggregates leads to architectural disruptions in tissues.
- Amyloid fibrils may also produce organ dysfunction via interaction with ligands and disruption of cell membranes.
- Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.[1]
- 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.[2]
- 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.[3]
References
- ↑ Riek, Roland; Eisenberg, David S. (2016). "The activities of amyloids from a structural perspective". Nature. 539 (7628): 227–235. doi:10.1038/nature20416. ISSN 0028-0836.
- ↑ Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy C, Merlini G (January 2012). "The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44". Blood. 119 (1): 144–50. doi:10.1182/blood-2011-05-355784. PMID 22067386.
- ↑ 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 (November 2015). "Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis". FASEB J. 29 (11): 4614–28. doi:10.1096/fj.15-272179. PMID 26220173.