Abstract
Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.
Keywords:
Alzheimer's disease; N‐BAR protein Bin1; actin binding; genetic risk factor; tau.
© 2017 The Authors.
MeSH terms
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Actin Cytoskeleton / genetics
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Actin Cytoskeleton / metabolism
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Actins / genetics*
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Actins / metabolism
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Binding Sites
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cloning, Molecular
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Disease Models, Animal
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / metabolism
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Gene Expression Regulation
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Humans
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Tauopathies / genetics*
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Tauopathies / metabolism
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Tauopathies / pathology
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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tau Proteins / genetics*
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tau Proteins / metabolism
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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BIN1 protein, human
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Carrier Proteins
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Drosophila Proteins
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MAPT protein, human
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Nuclear Proteins
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Protein Isoforms
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Recombinant Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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bicoid interacting protein 1, Drosophila
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tau Proteins