Current Pharmaceutical Design - Volume 14, Issue 30, 2008

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 charac Read More

Amyloid fibrils have been a critical subject in recent studies of proteins since they are associated with the pathology of more than 20 serious human diseases. Moreover, a variety of proteins and peptides not related to diseases are able to form amyloid fibrils or amyloid-like structures, implying that amyloid formation is a generic property of polypeptides. Although understanding the structure and formation of amyloid fibrils is cr Read More

Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T4) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfold Read More

Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid β-protein (Aβ), a 40-42 amino acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Aβ is formed through cleavage of the Aβ precursor protein by two endoproteinases, Read More

Lewy bodies (LBs) and Lewy neurites (LNs) in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein (∼14 kDa) named alpha-synuclein (αS). As the aggregation of αS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease- Read More

The polyglutamine (polyQ) diseases, including Huntington's disease and spinocerebellar ataxias, are classified as the protein misfolding neurodegenerative diseases like Alzheimer's and Parkinson's diseases, and they are caused by an abnormal expansion of the polyQ stretch in disease-causative proteins. Expanded polyQ stretches have been shown to undergo a conformational transition to a β-sheet-dominant st Read More

Amyloidosis is a clinical disorder caused by deposition of proteins that abnormally self-assemble into insoluble fibrils and impair organ function. More than 20 unrelated precursor proteins lose their native structure and misfold, leading to the formation of amyloid fibrils. The latter share cross-β core structure in vivo and in vitro and gain abnormal functions. Local amyloid deposition occurs in the central nervous system in Alzhei Read More