tailieunhanh - Báo cáo khoa học: Transthyretin and familial amyloidotic polyneuropathy Recent progress in understanding the molecular mechanism of neurodegeneration

Familial amyloidotic polyneuropathy (FAP) is an inherited autosomal dominant disease that is commonly caused by accumulation of deposits of transthyretin (TTR) amyloid around peripheral nerves. The only effective treatment for FAP is liver transplantation. | ỊFEBS Journal REVIEW ARTICLE Transthyretin and familial amyloidotic polyneuropathy Recent progress in understanding the molecular mechanism of neurodegeneration Xu Hou Marie-Isabel Aguilar and David H. Small Department of Biochemistry and Molecular Biology Monash University Clayton Victoria Australia Keywords transthyretin amyloidosis neurotoxicity neuropathy calcium neurodegeneration Correspondence D. H. Small Laboratory of Molecular Neurobiology Department of Biochemistry and Molecular Biology Monash University Clayton Campus Victoria 3800 Australia Fax 61 3 9905 3726 Tel 61 3 9905 1563 E-mail Received 3 December 2006 accepted 22 January 2007 doi Familial amyloidotic polyneuropathy FAP is an inherited autosomal dominant disease that is commonly caused by accumulation of deposits of transthyretin TTR amyloid around peripheral nerves. The only effective treatment for FAP is liver transplantation. However recent studies on TTR aggregation provide clues to the mechanism of the molecular pathogenesis of FAP and suggest new avenues for therapeutic intervention. It is increasingly recognized that there are common features of a number of protein-misfolding diseases that can lead to neurodegeneration. As for other amyloidogenic proteins the most toxic forms of aggregated TTR are likely to be the low-molecular-mass diffusible species and there is increasing evidence that this toxicity is mediated by disturbances in calcium homeostasis. This article reviews what is already known about the mechanism of TTR aggregation in FAP and describes how recent discoveries in other areas of amyloid research particularly Alzheimer s disease provide clues to the molecular pathogenesis of FAP. Introduction The term amyloidosis refers to disorders that are caused by the extracellular deposition of insoluble amyloid fibrils which are derived from the misfolding of proteins which under normal conditions are soluble. A large number