Date and place of birth : 11th May 1979, Tokyo, Japan
2010-present: Post-doctoral fellow in the research group of Dr. Evelina Chieregatti, Dept. Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
2002-2008: Ph.D from the Open University, UK, carried out in the laboratory of Prof. Peir Paolo Di Fiore, The European Institute of Oncology (IFOM-IEO), Milan, ItalyTitle of the PhD thesis: "A Study of the interactors of Eps15 Homology (EH) domain and the role of the EH network in the model system of Caenorhabditis elegans."
1998-2002: B.Sc 2:1 Hon.,Department of Biochemistry and Molecular Biology, University College London, University of London, UK.
1996-1998: International Baccalaureate Bilingual Diploma from the United Wolrd College of South East Asia, Singapore.
2009: Post-doctoral fellow in the research group of Dr. Evelina Chieregatti, DIBIT, Fondazione di San Raffaele, Milan, hosted in the laboratory of Dr. Carlo Sala, Institute of Neuroscience, CNR, Milan, Italy
2002: BSc thesis in the laboratories of Dr. Anne Ridley and of Dr. Rainer Cramer, Ludwig Institute of Cancer Research, London, UK. Project on identification of the phosphorylation of RhoE by ROCK using peptide mass finger printing with MALDI-ToF.
2000-2001: Industrial placement under the supervision of Dr. Klaus Schneider at the Department of Computational and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Harlow, UK.
Pathogenesis of Brain diseases, Molecular Neurobiology, Dept. of Neuroscience and Brain Technologies
Introduction: The presence of amyloid plaques, together with neurofibrillary tangles are considered to be the hallmarks of Alzheimer’s Disease (AD). A major consitutent of amyloid plaques is beta-amyloid peptide (Aß ), which derives from the proteolytic cleavage of a transmembrane protein, Amyloid Precursor Protein (APP). APP is first cleaved by the beta-secretase, BACE1 and the subsequent cleavage by the gamma secretase results in the generation of Aß .
1. Studying the effect of Aß peptide on cytoskeletal structures in neurites and growth cones of developing neurons.
A number of recent evidence points to synaptic loss and alterations in neurites morphology during the early development of AD. We are currently investigating the effect of Aß on the growth and retraction of neurites in cultured neurons.
This project focuses on the effect of monomeric Aß peptide on microtubules and actin cytoskeleton in cultured hippomcampal neurons. We follow the modification on actin dynamics and microtubule stability upon incubation with Aß by various imaging techniques as well as biochemical approach. We are currently studying the involvement of membrane microdomains, such as lipid raft, in the molecular mechanism underlying these cytoskeletal changes.
Together with Alpha-synuclein (α-syn), Aβ is also a major component of fibrillary lesions such as Lewy bodies and amyloid plaques of other neurodegenerative disorders, such as Parkinson’s disease (PD). A possible interplay between these two amyloidogenic components has been suggested by several studies. Using cultured neurons from wild type and from a deletion mutant of α-syn, we are also investigating the role of α-syn in the effects induced by Aß.
2. Identification of proteins that are internalized with Amyloid Precursor Protein (APP) by immunoisolation of APP-containing endocytic vesicles.
The intracellular localization of the cleavage of APP by BACE1 has long been a topic of debate. Although both proteins, APP and BACE1 are found as transmembrane proteins, numerous evidence suggest that amyloidogenesis increases with enhanced endocytosis. Early endosome is the first site of APP endocytic sorting, where APP has been shown to co-localize with BACE1 by more recent studies. Altered endosomal structures in AD brains have also become another characteristic of AD.
With these observations pointing towards the importance of APP-containing endosomes in the pathology of AD, we are using proteomic approaches to identify proteins of interest such as molecular motors,enzymes or adaptor proteins that may be found in the APP-containing endocytic vesicles.
Tsushima H, Emanuele, M, Esposito A, Polenghi A, Vassalli M, Barberis A, Difato F & Chieregatti E.
HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity. Nat. Commun. 6:7781 doi:10.1038/ncomms8781, 2015
Bellani S, Mescola A, Ronzitti G, Tsushima H, Tilve S, Canale C, Valtorta F, Chieregatti E.
GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein.
Cell Death Differ. doi:10/1038/cdd.2014.111, 2014
Tsushima H, Malabarba MG, Confalonieri S, Senic-Matuglia F, Verhoef LGGC, Bartocci C, D'Ario G, Cocito A, Di Fiore PP and Salcini AE (2013)
A Snapshot of the Physical and Functional Wiring of the Eps15 Homology Domain Network in the Nematode. PLoS ONE 8(2): e56383. doi:10.1371/journal.pone.0056383.
Beke S, Anjum F, Tsushima H, Ceseracciu L, Chieregatti E, Diaspro A, Athanassiou A, and Brandi F.
Towards excimer-laser-based stereolithography: a rapid process to fabricate rigid biodegradable photopolymer scaffolds
J. R. Soc. Interface doi:10.1098/rsif.2012.0300, 2012
Difato F, Tsushima H, Pesce M, Benfenati F, Blau A, and Chieregatti E.
The Formation of actin waves during regeneration after axonal lesion is enhanced by BDNF. Sci.Rep. 1, 183; DOI:10.1038/srep00183, 2011
Rose S, Malabarba MG, Krag C, Scultz A, Tsushima H, Di Fiore, P and Salcini AE.
Caenorhabditis elegans intersectin: a synaptic protein regulating neurotransmission. Mol.Biol.Cell, 18(12):5091-9, 2007