alpha-synuclein and Amyloid-Neuropathies--Familial

Amyloid-β (Aβ) fibrillogenesis and associated cyto/neurotoxicity are major pathological events and hallmarks in diseases such as Alzheimer's disease (AD). The understanding of Aβ molecular pathogenesis is currently a pharmacological target for rational drug design and discovery based on reduction of Aβ generation, inhibition of Aβ fibrillogenesis and aggregation, enhancement of Aβ clearance and amelioration of associated cytotoxicity. Molecular mechanisms for other amyloidoses, such as transthyretin amyloidosis, AL-amyloidosis, as well as α-synuclein and prion protein are also pharmacological targets for current drug therapy, design and discovery. We report on natural herbal compounds and extracts that are capable binding to and inhibiting different targets associated with AD and other amyloid-associated diseases, providing a basis for future therapeutic strategies. Many herbal compounds, including curcumin, galantamine, quercetin and other polyphenols, are under active investigation and hold considerable potential for future prophylactic and therapeutic treatment against AD and other neurodegenerative diseases, as well as systemic amyloid diseases. A common emerging theme throughout many studies is the anti-oxidant and anti-inflammatory properties of the compounds or herbal extracts under investigation, within the context of the inhibition of cyto/neurotoxicity and anti-amyloid activity.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Neuropathies, Familial; Animals; Drug Discovery; Humans; Multiprotein Complexes; Peptides; Phytotherapy; Plant Extracts; Prions

The accumulation of amyloid fibrils is a feature of amyloid diseases, where cell toxicity is due to soluble oligomeric species that precede fibril formation or are formed by fibril fragmentation, but the mechanism(s) of fragmentation is still unclear. Neutrophil-derived elastase and histones were found in amyloid deposits from patients with different systemic amyloidoses. Neutrophil extracellular traps (NETs) are key players in a death mechanism in which neutrophils release DNA traps decorated with proteins such as elastase and histones to entangle pathogens. Here, we asked whether NETs are triggered by amyloid fibrils, reasoning that because proteases are present in NETs, protease digestion of amyloid may generate soluble, cytotoxic species. We show that amyloid fibrils from three different sources (α-synuclein, Sup35, and transthyretin) induced NADPH oxidase-dependent NETs in vitro from human neutrophils. Surprisingly, NET-associated elastase digested amyloid fibrils into short species that were cytotoxic for BHK-21 and HepG2 cells. In tissue sections from patients with primary amyloidosis, we also observed the co-localization of NETs with amyloid deposits as well as with oligomers, which are probably derived from elastase-induced fibril degradation (amyloidolysis). These data reveal that release of NETs, so far described to be elicited by pathogens, can also be triggered by amyloid fibrils. Moreover, the involvement of NETs in amyloidoses might be crucial for the production of toxic species derived from fibril fragmentation.

Topics: Acetophenones; alpha-Synuclein; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Animals; Biomarkers; Cell Nucleus; Cell Survival; Chromatin; Cricetinae; Extracellular Space; Hep G2 Cells; Humans; Immunoglobulin Light-chain Amyloidosis; Lung; Mutation, Missense; NADPH Oxidases; Neutrophils; Onium Compounds; Pancreatic Elastase; Peptide Fragments; Prealbumin; Protein Structure, Quaternary; Proteolysis; Reactive Oxygen Species; Skin

The ubiquitin-proteasome system (UPS) has been associated with neurodegenerative disorders of intracellular protein aggregation. We have studied the UPS in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder caused by extracellular deposition of mutant transthyretin (TTR). The studies were conducted in TTR-synthesizing and non-synthesizing tissues from affected individuals, in transgenic mouse models for FAP, and in neuronal or Schwannoma cell lines cultured with TTR aggregates. In human FAP tissues presenting extracellular TTR aggregates, ubiquitin-protein conjugates were up-regulated, the proteasome levels were decreased and parkin and alpha-synuclein expression were both decreased. A similar response was detected in mouse models for TTR V30M or L55P. On the other hand, the liver, which normally synthesizes variant TTR V30M, did not show this response. Furthermore, transgenic mice immunized to decrease TTR deposition showed a significant reduction in ubiquitin levels and an increase in parkin and alpha-synuclein levels in comparison to control mice. Studies performed in cell lines with aggregates in the medium resulted in increased ubiquitin and decreased parkin levels. The overall results are indicative of TTR deposition as an external stimulus to an intracellular UPS response in FAP.

Topics: alpha-Synuclein; Amyloid Neuropathies, Familial; Animals; Disease Models, Animal; Extracellular Space; Humans; Immunization; Mice; Mice, Transgenic; Prealbumin; Proteasome Endopeptidase Complex; Salivary Glands; Skin; Tumor Cells, Cultured; Ubiquitin; Ubiquitin-Protein Ligases