Familial amyloidotic polyneuropathy: protein aggregation in the peripheral nervous system.
The molecular pathology underlying transthyretin (TTR)-related amyloidosis is largely unknown. It is possible that a common factor in the amyloidogenesis process exists among the different forms; this common factor can involve changes produced by mutations in the three-dimensional structure of TTR, rendering it prone to deposition as amyloid. This amyloidogenic potential, together with other yet unidentified factors, contribute to amyloid deposition. The factors that trigger fibril formation and/or neurodegeneration in TTR-related amyloidosis present central questions for which there are still no available clues. We recently showed in vitro that TTR fibrils trigger NF-kappaB activation, and subsequent studies identified some inflammatory and apoptotic pathways opening perspectives to understand the neurodegeneration process in familial amyloidotic polyneuropathy (FAP). It is current opinion that the modified TTR represents an amyloidogenic intermediate, which integrates the fibril structure; analyses of FAP fibrils have proved that TTR in the fibrils maintains a beta-conformation and have suggested that the TTR monomer is the building block in fibrils. This concept has been questioned recently by investigators, and only future studies on native and synthetic TTR fibrils using high-resolution structural techniques will further elucidate fibril structure and the aggregation pathway. Modulators responsible for phenotypic diversity can be addressed by mice transgenic for different human TTR mutations. Different lines are now available; incomplete penetrance and environmental influence on the deposition of mutant TTR has been observed. Therefore, these animals constitute important tools to address modulators of phenotypic expression and pathophysiological consequences of amyloid deposition at cellular/molecular levels. They are pivotal for testing potential drugs for TTR amyloidosis as well.
João Saraiva
Maria
M
Molecular Neurobiology, Instituto de Biologia Molecular e Celular, University of Porto, Portugal. mjsaraiv@ibmc.up.pt
Mendes Sousa
Mónica
M
Cardoso
Isabel
I
Fernandes
Rui
R
D000682:Amyloid / Q000096:biosynthesis*; D028227:Amyloid Neuropathies, Familial / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009454:Neurofibrils / Q000235:genetics / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000235:genetics
D000682:Amyloid; D011228:Prealbumin