Article

Pore-Forming Proteins Share Structural and Functional Homology with Amyloid Oligomers

Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
NeuroMolecular Medicine (Impact Factor: 3.89). 02/2007; 9(3):270-5. DOI: 10.1007/s12017-007-0003-6
Source: PubMed

ABSTRACT Degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are believed to be causally related to the accumulation of amyloid oligomers that exhibit a common structure and may be toxic by a common mechanism involving permeabilization of membranes. We discovered that amyloid oligomers and the pore-forming bacterial toxin, alpha-hemolysin (alpha HL), as well as human perforin from cytotoxic T lymphocytes, share a structural and functional homology at the level of their common reactivity with a conformation-dependent antibody that is specific for amyloid oligomers, A11. The alpha HL oligomeric pores and partially folded alpha HL protomer, but not the monomer alpha HL precursor reacts with A11 antibody. A11 antibody inhibits the hemolytic activity of alpha HL, indicating that the structural homology is functionally significant. Perforin oligomers were also recognized by A11. Amyloidogenic properties of alpha HL and perforin were confirmed spectroscopically and morphologically. These results indicate that pore forming proteins (PFP) and amyloid oligomers share structural homology and suggest that PFPs and amyloid oligomers share the same mechanism of membrane permeabilization.

3 Followers
 · 
100 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Amyloidogenic proteins generally form intermolecularly hydrogen-bonded β-sheet aggregates, including parallel, in-register β-sheets (recognized by antiserum OC), or antiparallel β-sheets, β-solenoids, β-barrels and β-cylindrins (recognized by antiserum A11). While these groups share many common properties, some amyloid sequences have been reported to form polymorphic structural variants or strains. We investigated the humoral immune response to Aβ42 fibrils and produced 23 OC-type monoclonal antibodies recognizing distinct epitopes differentially associated with polymorphic structural variants. These mOC antibodies define at least 18 different immunological profiles represented in aggregates of Aβ. All of the antibodies strongly prefer amyloid aggregates over monomer, indicating that they recognize conformational epitopes. Most of the antibodies react with N-terminal linear segments of Aβ, although many recognize a discontinuous epitope consisting of an amino terminal domain and a central domain. Several of the antibodies that recognize linear Aβ segments also react with fibrils formed from unrelated amyloid sequences, indicating that reactivity with linear segments of Aβ does not mean the antibody is sequence specific. The antibodies display strikingly different patterns of immunoreactivity in Alzheimer disease and transgenic mouse brain and identify spatially and temporally unique amyloid deposits. Our results indicate that the immune response to Aβ42 fibrils is diverse and reflects the structural polymorphisms in fibrillar amyloid structures. These polymorphisms may contribute to differences in toxicity and consequent effects on pathological processes. Thus, a single therapeutic monoclonal antibody may not be able to target all of the pathological aggregates necessary to make an impact on the overall disease process.
    Journal of Biological Chemistry 10/2014; DOI:10.1074/jbc.M114.594846 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In a number of neurological diseases including Parkinson's disease (PD), alpha-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of alpha-synuclein in vivo. The toxicity of alpha-synuclein is popularly attributed to the formation of " toxic oligomers " : a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of alpha-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic alpha-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between alpha-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of alpha-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.
  • Source