Wild-type (senile) amyloidosis pathophysiology
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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
Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in the different connective tissues.
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.