Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
-
Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. ⋯ Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.
-
Mounting evidence points to soluble peptide oligomers as the primary agents in various amyloid and prion diseases. Multiple mechanisms appear to contribute to the cytotoxic effects of these oligomers. Here, an additional, general mechanism is proposed - that soluble amyloid peptide oligomers serve as "all-purpose"beta strands that can interact with transiently unfolded or nascent proteins where interior beta-sheet edges are exposed. ⋯ If the bound amyloid oligomer dissociates at some point after the misfolded protein is committed to the UPS pathway, the oligomer could then repeat the process, adding a catalytic aspect to the misfolding mechanism. Direct proof of this proposed mechanism requires detection of amyloid oligomer-beta-sheet protein complexes, and a co-immunoprecipitation experiment is proposed. This hypothesis supports therapies that increase amyloid oligomer degradation or sequestration, as well as therapies that upregulate chaperone activity, for combating amyloid-related diseases.