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Ayuko Sakane

Bio: Ayuko Sakane is an academic researcher from University of Tokushima. The author has contributed to research in topics: Cytoskeleton & Actin cytoskeleton. The author has an hindex of 11, co-authored 19 publications receiving 575 citations.

Papers
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Journal ArticleDOI
TL;DR: Rubicon, a subunit of the Beclin 1-PI3-kinase complex and its homologue, PLEKHM1, negatively regulate endocytic pathway through the interaction with Rab7.
Abstract: The endocytic and autophagic pathways are involved in the membrane trafficking of exogenous and endogenous materials to lysosomes. However, the mechanisms that regulate these pathways are largely unknown. We previously reported that Rubicon, a Beclin 1–binding protein, negatively regulates both the autophagic and endocytic pathways by unidentified mechanisms. In this study, we performed database searches to identify potential Rubicon homologues that share the common C-terminal domain, termed the RH domain. One of them, PLEKHM1, the causative gene of osteopetrosis, also suppresses endocytic transport but not autophagosome maturation. Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain, and this interaction is critical for their function. Furthermore, we show that Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase.

135 citations

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TL;DR: It is demonstrated by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kines in-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components, and it is reported that assembly of kinesIn-1 C and APP in this vesicles type requires Rab3GTPase activity.
Abstract: The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by beta- and gamma-secretases leading to accumulation of beta-amyloid (Abeta) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by alpha-secretases prevents Abeta generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP in transport vesicles by alpha-secretase activity, likely mediated by ADAM10. Together, these data indicate that maturation of APP transport vesicles, including recruitment of conventional kinesin, requires Rab3 GTPase activity.

105 citations

Journal ArticleDOI
TL;DR: Rab3 GAP regulates synaptic transmission and plasticity by limiting the amount of the GTP-bound form of Rab3A.
Abstract: Rab3A small G protein is a member of the Rab family and is most abundant in the brain, where it is localized on synaptic vesicles. Evidence is accumulating that Rab3A plays a key role in neurotransmitter release and synaptic plasticity. Rab3A cycles between the GDP-bound inactive and GTP-bound active forms, and this change in activity is associated with the trafficking cycle of synaptic vesicles at nerve terminals. Rab3 GTPase-activating protein (GAP) stimulates the GTPase activity of Rab3A and is expected to determine the timing of the dissociation of Rab3A from synaptic vesicles, which may be coupled with synaptic vesicle exocytosis. Rab3 GAP consists of two subunits: the catalytic subunit p130 and the noncatalytic subunit p150. Recently, mutations in p130 were found to cause Warburg Micro syndrome with severe mental retardation. Here, we generated p130-deficient mice and found that the GTP-bound form of Rab3A accumulated in the brain. Loss of p130 in mice resulted in inhibition of Ca 2+ -dependent glutamate release from cerebrocortical synaptosomes and altered short-term plasticity in the hippocampal CA1 region. Thus, Rab3 GAP regulates synaptic transmission and plasticity by limiting the amount of the GTP-bound form of Rab3A.

97 citations

Journal ArticleDOI
TL;DR: It is suggested that Rab13 and JRAB/MICAL-L2 may act to transfer actinin-4 from the cell body to the tips of neurites, where actin in-4 is involved in the reorganization of the actin cytoskeleton which results in neurite outgrowth.
Abstract: Neurite outgrowth is the first step in the processes of neuronal differentiation and regeneration and leads to synaptic polarization and plasticity. Rab13 small G protein shows an increased mRNA expression level during neuronal regeneration; it is therefore thought to be involved in this process. We previously identified JRAB (junctional Rab13-binding protein)/MICAL-L2 (molecules interacting with CasL-like 2) as a novel Rab13 effector protein. Here, we show that Rab13 regulates neurite outgrowth in the rat pheochromocytoma cell line PC12 through an interaction with JRAB/MICAL-L2. The expression of JRAB/MICAL-L2 alone inhibits neurite outgrowth, whereas coexpression of the dominant active form of Rab13 rescues this effect. We also demonstrate an intramolecular interaction between the N-terminal calponin-homology (CH) and LIM domains of JRAB/MICAL-L2 and the C-terminal coiled-coil domain. Finally, we show that the binding of Rab13 to JRAB/MICAL-L2 stimulates the interaction of JRAB/MICAL-L2 with actinin-4, an actin-binding protein, which localizes to the cell body and the tips of the neurites in PC12 cells. These results suggest that Rab13 and JRAB/MICAL-L2 may act to transfer actinin-4 from the cell body to the tips of neurites, where actinin-4 is involved in the reorganization of the actin cytoskeleton which results in neurite outgrowth.

71 citations

Journal ArticleDOI
TL;DR: The results suggest that the Doc2α-Μunc13-4 system regulates Ca2+-dependent secretory lysosome exocytosis in mast cells.
Abstract: The Doc2 family comprises the brain-specific Doc2α and the ubiquitous Doc2β and Doc2γ. With the exception of Doc2γ, these proteins exhibit Ca 2+ -dependent phospholipid-binding activity in their Ca 2+ -binding C2A domain and are thought to be important for Ca 2+ -dependent regulated exocytosis. In excitatory neurons, Doc2α interacts with Munc13-1, a member of the Munc13 family, through its N-terminal Munc13-1-interacting domain and the Doc2α-Munc13-1 system is implicated in Ca 2+ -dependent synaptic vesicle exocytosis. The Munc13 family comprises the brain-specific Munc13-1, Munc13-2, and Munc13-3, and the non-neuronal Munc13-4. We previously showed that Munc13-4 is involved in Ca 2+ -dependent secretory lysosome exocytosis in mast cells, but the involvement of Doc2 in this process is not determined. In the present study, we found that Doc2α but not Doc2β was endogenously expressed in the RBL-2H3 mast cell line. Doc2α colocalized with Munc13-4 on secretory lysosomes, and interacted with Munc13-4 through its two regions, the N terminus containing the Munc13-1-interacting domain and the C terminus containing the Ca 2+ -binding C2B domain. In RBL-2H3 cells, Ca 2+ -dependent secretory lysosome exocytosis was inhibited by expression of the Doc2α mutant lacking either of the Munc13-4-binding regions and the inhibition was suppressed by coexpression of Munc13-4. Knockdown of endogenous Doc2α also reduced Ca 2+ -dependent secretory lysosome exocytosis, which was rescued by re-expression of human Doc2α but not by its mutant that could not bind to Munc13-4. Moreover, Ca 2+ -dependent secretory lysosome exocytosis was severely reduced in bone marrow-derived mast cells from Doc2α knockout mice. These results suggest that the Doc2α-Μunc13-4 system regulates Ca 2+ -dependent secretory lysosome exocytosis in mast cells.

54 citations


Cited by
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Journal ArticleDOI
TL;DR: The maturation programme entails a dramatic transformation of these dynamic organelles disconnecting them functionally and spatially from early endosomes and preparing them for their unidirectional role as a feeder pathway to lysosomes.
Abstract: Being deeply connected to signalling, cell dynamics, growth, regulation, and defence, endocytic processes are linked to almost all aspects of cell life and disease. In this review, we focus on endosomes in the classical endocytic pathway, and on the programme of changes that lead to the formation and maturation of late endosomes/multivesicular bodies. The maturation programme entails a dramatic transformation of these dynamic organelles disconnecting them functionally and spatially from early endosomes and preparing them for their unidirectional role as a feeder pathway to lysosomes.

1,859 citations

Journal ArticleDOI
James J. Lee1, Robbee Wedow2, Aysu Okbay3, Edward Kong4, Omeed Maghzian4, Meghan Zacher4, Tuan Anh Nguyen-Viet5, Peter Bowers4, Julia Sidorenko6, Julia Sidorenko7, Richard Karlsson Linnér3, Richard Karlsson Linnér8, Mark Alan Fontana9, Mark Alan Fontana5, Tushar Kundu5, Chanwook Lee4, Hui Li4, Ruoxi Li5, Rebecca Royer5, Pascal Timshel10, Pascal Timshel11, Raymond K. Walters4, Raymond K. Walters12, Emily A. Willoughby1, Loic Yengo6, Maris Alver7, Yanchun Bao13, David W. Clark14, Felix R. Day15, Nicholas A. Furlotte, Peter K. Joshi14, Peter K. Joshi16, Kathryn E. Kemper6, Aaron Kleinman, Claudia Langenberg15, Reedik Mägi7, Joey W. Trampush5, Shefali S. Verma17, Yang Wu6, Max Lam, Jing Hua Zhao15, Zhili Zheng6, Zhili Zheng18, Jason D. Boardman2, Harry Campbell14, Jeremy Freese19, Kathleen Mullan Harris20, Caroline Hayward14, Pamela Herd21, Pamela Herd13, Meena Kumari13, Todd Lencz22, Todd Lencz23, Jian'an Luan15, Anil K. Malhotra23, Anil K. Malhotra22, Andres Metspalu7, Lili Milani7, Ken K. Ong15, John R. B. Perry15, David J. Porteous14, Marylyn D. Ritchie17, Melissa C. Smart14, Blair H. Smith24, Joyce Y. Tung, Nicholas J. Wareham15, James F. Wilson14, Jonathan P. Beauchamp25, Dalton Conley26, Tõnu Esko7, Steven F. Lehrer27, Steven F. Lehrer28, Steven F. Lehrer29, Patrik K. E. Magnusson30, Sven Oskarsson31, Tune H. Pers11, Tune H. Pers10, Matthew R. Robinson6, Matthew R. Robinson32, Kevin Thom33, Chelsea Watson5, Christopher F. Chabris17, Michelle N. Meyer17, David Laibson4, Jian Yang6, Magnus Johannesson34, Philipp Koellinger3, Philipp Koellinger8, Patrick Turley12, Patrick Turley4, Peter M. Visscher6, Daniel J. Benjamin5, Daniel J. Benjamin28, David Cesarini33, David Cesarini28 
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

1,658 citations

Journal ArticleDOI
TL;DR: An overview of the role of autophagy in neurodegenerative disease is provided, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease.
Abstract: This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases.

1,643 citations

Journal ArticleDOI
TL;DR: This chapter outlines how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active and illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.
Abstract: Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.

922 citations

Journal ArticleDOI
TL;DR: This review will define this process and the cellular pathways required, from the formation of the double membrane to the fusion with lysosomes in molecular terms, and in particular highlight the recent progress in understanding of this complex process.
Abstract: Macroautophagy/autophagy is an essential, conserved self-eating process that cells perform to allow degradation of intracellular components, including soluble proteins, aggregated proteins, organelles, macromolecular complexes, and foreign bodies. The process requires formation of a double-membrane structure containing the sequestered cytoplasmic material, the autophagosome, that ultimately fuses with the lysosome. This review will define this process and the cellular pathways required, from the formation of the double membrane to the fusion with lysosomes in molecular terms, and in particular highlight the recent progress in our understanding of this complex process.

895 citations