Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant neurodegenerative disorder related to the systemic deposition of mutated transthyretin (TTR) amyloid fibrils, particularly in peripheral nervous system (PNS). Recently, evidence for the presence of toxic non-fibrillar TTR aggregates early in FAP nerves constituted a first step to unravel molecular signaling related to neurodegeneration in FAP. The toxic nature of TTR non-fibrillar aggregates, and not mature TTR fibrils, was evidenced by their ability to induce the expression of oxidative stress and inflammation-related molecules in neuronal cells, driving them into apoptotic pathways. How these TTR aggregates exert their effects is debatable; interaction with cellular receptors, namely the receptor for advanced glycation endproducts is a probable candidate mechanism. The pathology and the yet unknown molecular signaling mechanisms responsible for neurodegeneration in FAP will be discussed.
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9. References
Almeida, M.R., Macedo, B., Cardoso, I., Alves, I., Valencia, G., Arsequell, G., Planas, A. and Saraiva, M.J., 2004, Effective and selective action of a iodinated diflunisal derivative in transthyretin binding and tetramer stabilization in serum from familial amyloidotic polyneuropathy patients. Biochem. J. 381: 351.
Alves, I.L., Altland, K., Almeida, M.R., Winter, P. and Saraiva, M.J.M., 1997, Screening and biochemical characterization of transthyretin variants in the Portuguese population. Hum. Mutat. 9: 226.
Andersson, R., 1970, Hereditary amyloidosis with polyneuropathy. Acta Med. Scand. 188: 85.
Andrade, C., 1952, A peculiar form of peripheral neuropathy. Familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 175: 408.
Araki, S., 1984, Type I familial amyloidotic polyneuropathy (Japanese type). Brain Develop. 6: 128.
Benditt, E.P., Eriksen, N., Hermodson, M.A. and Ericsson, L.H., 1971, The major proteins of human and monkey substance: common properties including unusual N-terminal amino acid sequences. FEBS Lett. 19: 169.
Blake, C.C.F., Geisow, M.J., Swan, I.D.A., Rérat, C. and Rérat, B., 1974, Structure of human plasma prealbumin at 2.5 A resolution. A preliminary report on the polypeptide chain conformation quaternary structure and thyroxine binding. J. Mol. Biol. 88: 1.
Cardoso, I., Goldsbury, C., Muller, S.A., Olivieri, V., Wirtz, S., Damas, A.M., Aebi, U. and Saraiva, M.J., 2002, Transthyretin fibrillogenesis entails the assembly of monomers: A molecular model for in vitro assembled transthyretin amyloid-like fibrils. J. Mol. Biol. 317: 687.
Cardoso, I., Merlini, G. and Saraiva, M.J., 2003, A4’-iodo-4’-Deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing non-cytotoxic species. Screening for TTR fibril disrupters. FASEB J. 17: 803.
Cardoso, I. and Saraiva, M.J., 2006, Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 20: 234.
Coelho, T., Chorão, R., Sousa, A., Alves, I.L., Torres, M.F. and Saraiva, M.J.M., 1996, Compound heterozygotes of transthyretin Met 30 and transthyretin Met 119 are protected from the devastating effects of familial amyloid polyneuropathy. Neuromuscular Disord. (Suppl) 6: S20.
Coimbra, A. and Andrade, C., 1971, Familial amyloid polyneuropathy: and electron microscope study of peripheral nerve in five cases. I. Interstitial changes. Brain 94: 199.
Eanes, E.D. and Glenner, G.G., 1968, X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16: 673.
Glenner, G.G., Terry, W.D., Harada, M., Isersky, C. and Page, D.L., 1971, Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analysis. Science 172: 1150.
Goldsteins, G., Persson, H., Andersson, K., Olofsson, A., Dacklin, I., Edvinsson Saraiva, M.J. and Lundgren, E., 1999, Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants. Proc. Natl Acad. Sci. USA 96: 3108.
Holmgren, G., Steen, L., Ekstedt, J., Groth, C.G., Ericzon, B.G., Eriksson, S., Andersen, O., Karlberg, I., Norden, G. and Nakazato, M., 1991, Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin. Genet. 40: 242.
Holmgren, G., Ericzon, B.G., Groth, C.G., Steen, L., Suhr, O., Andersen, O., Wallin, B.G., Seymour, A., Richardson, S., Hawkins, P.N. and Pepys, M.B., 1993, Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341: 1113.
Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S. and Buxbaum, J., 1997, Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N. Engl. J. Med. 336: 466.
Kohno, K., Palha, J.A., Miyakawa, K., Saraiva, M.J., Ito, S., Mabuchu, T., Blaner, W.S., Iijima, H., Tsukahara, S., Episkopou, V., Gottesman, M.E., Shimada, K., Takahashi, K., Yamamura, K. and Maeda, S., 1997, Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy. Am. J. Pathol. 150: 1497.
Lewis, W.D. and Skinner, M., 1994, Liver transplantation for familial amyloidotic polyneuropathy: a potentially curative treatment. Amyloid: Int. J. Exp. Clin. Invest. 1: 143.
Monteiro, F., Sousa, M.M., Cardoso, I., Barbas do Amaral, J., Guimarães, A. and Saraiva, M.J., 2006, Activation of ERK1/2 MAP kinases in Familial Amyloidotic Polyneuropathy. J. Neurochem. 97: 151.
Moses, A.C., Rosen, H.N., Moller, D.E., Tsuzaki, S., Haddow, J.E., Lawlor, J., Liepnieks, J.J., Nichols, W.C. and Benson, M.D., 1990, A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J. Clin. Invest. 86: 2025.
Munar-Qués, M., Costa, P.P., Saraiva, M.J.M., Farré, C.V., Bernat, C.M., Luna, C.C. and Alberti, J.F.F., 1997, Familial amyloidotic polyneuropathy. TTR Met 30 in Majorca (Spain). Amyloid 4: 181.
Palha, J.A., Moreira, P., Olofsson, A., Lundgren, E. and Saraiva, M.J., 2001, Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy. J. Mol. Med. 78: 703.
Quintas, A., Vaz, D., Cardoso, I., Saraiva, M.J. and Brito, R.M., 2001, Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants. J. Biol. Chem. 276: 27207.
Saraiva, M.J.M., Birken, S., Costa, P.P. and Goodman, D.S., 1984, Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of a molecular abnormality in transthyretin (prealbumin). J. Clin. Invest. 74: 104.
Sasaki, H., Yoshioka, N., Takagi, Y. and Sakaki, Y., 1985, Structure of the chromosomal gene for human serum prealbumin. Gene 37: 191.
Schmidt, A.M., Yan, S.D., Yan, S.F. and Stern, D.M., 2000, The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498: 99.
Sebastião, M.P., Saraiva, M.J. and Damas, A.M., 1998, The crystal structure of amyloidogenic Leu55 --> Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils. J. Biol. Chem. 273: 24715.
Soprano, D.R., Herbert, J., Soprano, K.J., Schon, E.A. and Goodman, D.S., 1985, Demonstration of transthyretin mRNA in the brain and other extrahepatic tissues in the rat. J. Biol. Chem. 260: 11793.
Sousa, M.M., Yan, S.D., Stern, D., Saraiva, M.J., 2000, Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation. Lab. Invest. 80: 1101.
Sousa, M.M., Cardoso, I., Fernandes, R., Guimarães, A. and Saraiva, M.J., 2001, Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of non-fibrillar aggregates. Am. J. Pathol. 159: 1993.
Sousa, M.M., Yan, S.D., Fernandes, R., Guimarães, A., Stern, D. and Saraiva, M.J.M., 2001a, Familial amyloid polyneuropathy: RAGE-dependent triggering of neuronal inflammatory and apoptotic pathways. J. Neurosci. 21: 7576.
Sousa, M.M., Barbas do Amaral, J., Guimarães, A. and Saraiva, M.J., 2005, Upregulation of the extracellular matrix remodelling genes, biglycan, neutrophil gelatinase-associated lipocalin and matrix metalloproteinase-9 in familial amyloid polyneuropathy. FASEB J. 19: 124.
Terazaki, H., Ando, Y., Fernandes, R., Yamamura, K., Maeda, S. and Saraiva, M.J., 2006, Immunization in familial amyloidotic polyneuropathy: Counteracting deposition by immunization with a Y78F TTR mutant. Lab. Invest. 86: 23.
Wallace, M.R., Naylor, S.L., Kluve-Beckerman, B., Long, G.L., McDonald, L., Shows, T.B. and Benson, M.D., 1985, Localization of the human prealbumin gene to chromosome 18, Biochem. Biophys. Res. Commun. 129: 753.
Westermark, P., Sletten, K., Johansson, B. and Cornwell, G.G. III, 1990, Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc. Natl Acad. Sci. USA 87: 2843.
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Saraiva, M.J. (2007). Inflammation and Apoptotic Pathways in the Peripheral Nervous System Related to Protein Misfolding. In: Malva, J.O., Rego, A.C., Cunha, R.A., Oliveira, C.R. (eds) Interaction Between Neurons and Glia in Aging and Disease. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-70830-0_12
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