Editorial [Hot Topic: Anti-Amyloidogenic/Protein-Misfolding Therapies in Amyloidosis and Other Protein-Misfolding Disorders (Executive Editor: Masahito Yamada)]

Amyloidosis is a pathological condition where proteins with diverse chemical composition are extracellularly deposited as fibrils in the brain, heart, kidney, liver, pancreas, nerves, and other tissues or organs resulting in their serious dysfunctions. Misfolding or conformational changes of normally soluble proteins lead to pathological deposition of fibrillar proteins with a cross-β-pleated configuration. In addition to amyloidosis characterized by extracellular fibril deposition, protein-misfolding or conformational disorders include diseases characterized by intracellular deposition of fibrillar structures (inclusion bodies) such as Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and polyglutamine diseases of the brain. Amyloidosis is classified to (1) systemic amyloidosis that involves various organs in the body, and (2) localized amyloidosis that affects a specific organ. According to the amyloidogenic protein, systemic amyloidosis is classified to several types including immunoglobulin (AL), AA, transthyretin (TTR) [familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis (SSA)], and β2-microglobulin (β2-m) amyloidoses (dialysis-related amyloidosis). An example of localized amyloidosis is brain amyloidosis including amyloid β-protein (Aβ) [Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA)] and prion protein amyloidoses (Creutzfeldt-Jakob disease and related disorders). A pathologic process to amyloid deposition includes: (1) production of amyloid precursor proteins, (2) processing of the precursor proteins to amyloidogenic proteins (monomers), and (3) protein misfolding (conformational change) and aggregation, finally resulting in deposition of the fibrillar proteins. The protein misfolding and aggregation is an essential process, shared by different types of amyloidoses and other protein-misfolding disorders. In this process, oligomeric forms or intermediate states have been reported to be more toxic than mature fibrils in Alzheimer's disease or other protein-misfolding disorders. Previously, a disease-modifying therapy for amyloidosis had been largely limited to the suppression of production of amyloid precursor proteins; for example, familial TTR amyloidosis caused by mutations of the TTR gene has been treated by transplantation of the liver, TTR-producing organ. Recently, however, anti-amyloidogenic or anit-protein misfolding therapies that target the process of protein misfolding and aggregation have been under development, and clinical trials with these therapies have been started in some diseases. In this issue, the experts in this research field discuss molecular basis and therapeutic potentials of anti-amyloidogenic/proteinmisfolding therapies in these disorders. In the first article, Dr. Goto and his colleagues [1] address recent advances in the structural study of structure, formation, and propagation of amyloid fibrils. On the basis of various approaches including solidstate nuclear magnetic resonance (NMR), hydrogen/deuterium exchange of amide protons, and total internal reflection fluorescence microscopy, convincing models of amyloid structures, their formation, and propagation have emerged. In the second article, Dr. Sekijima and his colleagues [2] discuss the pathogenesis of TTR amyloidosis (FAP/SSA), and suggest new strategies for therapeutic interventions for replacement of liver transplantation that is currently the only effective treatment for FAP. The new strategies include stabilization of TTR tetramer (native state) by small molecule binding in order to prevent its dissociation to misfolded monomers. In the third article, Dr. Teplow and his colleagues [3] discuss therapeutic strategies against AD, the most common neurodegerative disease in the elderly. They summarize recent efforts to develop disease-modifying therapeutic agents targeting Aβ assembly, including immunotherapy, nutraceuticals, and a variety of candidate molecules, of which some have progressed to phase III clinical trials, and the others are less mature, but have therapeutic potential. In the fourth article, Dr. Ono and our group [4] focus on aggregation of α-synuclein (αS) which is a major component of Lewy bodies, neuropathological hallmarks of PD/DLB. Some compounds such as polyphenols are found with anti-fibrillogenic, antioligomeric, and fibril-destabilizing effects for αS, indicating that they could be key molecules for development of the preventives and therapeutics for PD/DLB and other αS-related disorders (α-synucleinopathies). In the fifth article, Drs. Nagai and Popiel [5] deal with the polyglutamine (polyQ) diseases, including Huntington’s disease and spinocerebellar ataxias, which are caused by an abnormal expansion of the polyQ stretch in disease-causative proteins.