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Coronavirus: aggiornamenti per la comunità universitaria

Dott.ssa Martina Lorenzati

Tesi di dottorato

Uncovering novel players in oligodendroglial physiopathology and heterogeneity

Attività di ricerca

c-Jun N-terminal Kinase 1 (JNK1) modulates oligodendrocyte progenitor cell architecture, proliferation and myelination

During the Central Nervous System ontogenesis, myelinating oligodendrocytes arise from highly ramified and proliferative precursors called oligodendrocyte progenitor cells (OPCs). OPC architecture, proliferation and oligodendro-/myelino-genesis are finely regulated by the interplay of cell-intrinsic and extrinsic factors. A variety of extrinsic cues converge on the extracellular signal regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway. Here we found that the germinal ablation of the MAPK c-Jun N-Terminal Kinase isoform 1 (JNK1) results in a significant reduction of myelin basic protein in the cerebral cortex and corpus callosum at both postnatal and adult stages. Myelin alterations are accompanied by higher OPC density and proliferation during the first weeks of life, consistent with a transient alteration of mechanisms regulating OPC self-renewal and differentiation. JNK1 KO OPCs also show smaller occupancy territories and a less complex branching architecture in vivo. Notably, these latter phenotypes are recapitulated in pure cultures of JNK1 KO OPCs and of WT OPCs treated with the JNK inhibitor D-JNKI-1. Our results unveil a novel player in the complex regulation of OPC biology, showing that JNK1 ablation results in persistent myelin abnormalities in vivo and determines alterations of OPC proliferation and branching architecture.

Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy

Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a therapeutic strategy for downregulating a single mutant allele with minimal suppression of the corresponding wild-type allele. This approach has been effectively used to target autosomal dominant mutations and single nucleotide polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we propose ASP-siRNA as a preferable choice to target duplicated disease genes, avoiding potentially harmful excessive downregulation. As a proof-of-concept, we studied autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) due to lamin B1 (LMNB1) duplication, a hereditary, progressive and fatal disorder affecting myelin in the CNS. Using a reporter system, we screened the most efficient ASP-siRNAs preferentially targeting one of the alleles at rs1051644 (average minor allele frequency: 0.45) located in the 3′ untranslated region of the gene. We identified four siRNAs with a high efficacy and allele-specificity, which were tested in ADLD patient-derived fibroblasts. Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels. Furthermore, small interfering RNA treatment abrogates the ADLD-specific phenotypes in fibroblasts and in two disease-relevant cellular models: murine oligodendrocytes overexpressing human LMNB1, and neurons directly reprogrammed from patients’ fibroblasts. In conclusion, we demonstrated that ASP-silencing by RNA interference is a suitable and promising therapeutic option for ADLD. Moreover, our results have a broad translational value extending to several pathological conditions linked to gene-gain in copy number variations.

Citron-kinase deletion unveils inherent molecular and functional heterogeneity in dorsal and ventral OPCs of the mouse forebrain

Vertebrate neurons are enormously diversified in morphology, neurochemical profile, function and susceptibility to injury. Diversity is instead much less established for neuroglia cells, despite observations of distinct functional properties and the identification of distinct embryonic sources for subsets of astroglia and oligodendroglia. In particular, whether, depending on their developmental origin, glial cell subpopulations may differ in molecular features or in their ability to contribute/respond to pathological conditions, is still not understood. We tackled this issue by studying a mouse model of human microlissencephaly, where the germinal ablation of Citron-kinase (Cit-K, a citoskeleton regulator involved in cell division and DNA repair) resulted in profound myelination defects and triggered distinct responses in telencephalic dorsal oligodendrocyte progenitor cells (dOPCs; i.e. populating the dorsal cortex and corpus callosum, and generated perinatally by Emx1+ progenitors in the dorsal subventricular zone) and ventral OPCs (vOPCs; i.e. located in the striatum and hypothalamus and generated during the embryonic life in the preoptica area and ganglionic eminences). Both populations showed high levels of DNA damage. However, Cit-K KO dOPCs underwent depletion, whereas vOPCs persisted and displayed a senescent phenotype. Such differential sensitivity depended on a distinct intrinsic capability to set up Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated anti-oxidant defenses. Notably, also WT dOPCs showed a higher intrinsic vulnerability to DNA damage induced by cisplatin, that could be counteracted by an anti-oxidant supplementation. These data provide novel evidence of molecular and functional heterogeneity in OPC subsets and indicate that distinct postnatal OPC populations may be differentially vulnerable to pathological conditions associated with DNA damage and oxidative stress.

GHIBAUDI Matilde*, LORENZATI Martina* et al., Current and Novel Strategies for Biomarkers Detection in Neurodegenerative Diseases: Future Graphene-Based Applications. DigitCult - Scientific Journal on Digital Cultures, [S.l.], v. 2, n. 2, p. 51-71, mar. 2018. ISSN 2531-5994. *co-first author

Elisa Giorgio, Martina Lorenzati, Pia Rivetti di Val Cervo, Alessandro Brussino, Manuel Cernigoj, Edoardo Della Sala, Anna Bartoletti Stella, Marta Ferrero, Massimiliano Caiazzo, Sabina Capellari, Pietro Cortelli, Luciano Conti, Elena Cattaneo, Annalisa Buffo, Alfredo Brusco, Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy,Brain, awz139, https://doi.org/10.1093/brain/awz139.

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Role of JNK1 in oligodendrocyte differentiation" - Oral presentation, G.I.S.N. Congress - November 2015 - Rome (Italy).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Role of JNK1 in oligodendrocyte differentiation" - Poster presentationISDN2016 Congress - May 2016 - Antibes (France).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Oral presentation, G.I.S.N. Congress - November 2017 - Bologna (Italy).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Poster presentationSINS (Italian Society for the Neurosciences) Congress – February 2018 - Naples (Italy).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Poster presentation, NeuroPsicoTo Fest Congress – June 2018 - Turin (Italy).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Poster presentation, BRAYN Congress – June 2018 - Genova (Italy).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Poster presentation, FENS Congress – July 2018 - Berlin (Germany).

Giorgio E., Lorenzati M., Rivetti di Val Cervo P., Brussino A., Cernigoj M., Della Sala E., Bartoletti Stella A., Ferrero M., Caiazzo M., Capellari S., Cortelli P., Conti L., Cattaneo E., Buffo A., Brusco A. "Preclinical validation of allele-specific silencing in patient-derived directly reprogrammed neuronal cell lines as effective treatment for Autosomal Dominant LeukoDystrophy" - European Human Genetics Conference - June 2019 - Gothemburg (Sweden) - Oral Presentation of Giorgio E.

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Poster presentation, European Glia Meeting 2019 Congress – July 2019 - Porto (Portugal).

Lorenzati M., Boda E., Borsello T., Buffo A. and Vercelli A. "Axo-glial interplay in oligodendrocyte specification and myelination: role of JNK1" - Oral presentation, BRAYN Congress – November 2019 - Milan (Italy).

Lorenzati M., Parolisi R., Harding B., Pallavicini GM., Bonfanti L., Di Cunto F., Buffo A., Boda E. "Are oligodendrocyte progenitors all born equal? A lesson from a microcephaly model" - Poster presentation, BRAYN Congress – November 2019 - Milan (Italy).

Marchetti V., Astigiano C., Fornaro G., Zen C., Lorenzati M., Parolisi R., Pallavicini GM., Harding B., Di Cunto F., Buffo A., Boda E. "In search for druggable mechanisms in MCPH17 primary microcephaly: a preliminary study on the effects of a postnatal antioxidant treatment" - BRAYN Congress – November 2019 - Milan (Italy) - Poster presentation of Marchetti V.

Astigiano C., Fornaro G., Zen C., Lorenzati M., Parolisi R., Harding B., Di Cunto F., Buffo A., Boda E. "Understanding the molecular bases of myelination defects in the microcephalic Citron-K KO mouse: a role for secreted Wnt inhibitors?" - BRAYN Congress – November 2019 - Milan (Italy) - Poster presentation of Astigiano C.

Lorenzati M., Boda E., Borsello T., Herdegen T., Buffo A. and Vercelli A. "c-Jun N-terminal Kinase 1 (JNK1) modulates oligodendrocyte progenitor cell architecture, proliferation and myelination" - Oral presentation, 2° incontro nazionale MORFOLOGIA E DINTORNI – February 2020 - Turin (Italy).

G.I.S.N. Congress - November, 2015 - Rome (Italy).

ISDN2016 Congress - May 2016 - Antibes (France).

G.I.S.N. Congress - November 2017 - Bologna (Italy).

SINS (Italian Society for the Neurosciences) Congress – February 2018 - Naples (Italy).

NeuroPsicoTo Fest Congress – June 2018 - Turin (Italy).

BRAYN Congress – June 2018 - Genova (Italy).

FENS Congress – July 2018 - Berlin (Germany).

European Glia Meeting 2019 Congress – July 2019 - Porto (Portugal).

BRAYN Congress – November 2019 - Milan (Italy).

2° incontro nazionale MORFOLOGIA E DINTORNI – February 2020 - Turin (Italy).

SINS (Italian Society for the Neurosciences) Congress – Semptember 2020 - online.

Glial cell-neuron crosstalk in CNS health and disease Workshop - October 2020 - online.

2016

"FOCUS on CDKL5" Teachers: Elisabetta Ciani, Stuart Cobb, Bianca Di Filippis, Maurizio Giustetto, Charlotte Kilstrup-Nielsen, Tommaso Pizzorusso, Sila Ultanir - Auditorium Banca Popolare di Novara, Piazza San Carlo 196 - November 18th 2016, Turin.

2017

"Building your carreer in the EU", Biblioteca Arturo Graf, Rettorato - Via Po 17, Turin - March 1st 2017.

"Principal techniques for project design", Biblioteca Arturo Graf, Rettorato - Via Po 17, Turin - March 1st 2017.

"Orientamento al mondo del lavoro fuori dall'Università" Scuole di Dottorato dell'Università di Torino  in collaborazione con la fondazione Sodalitas e l'Organizzazione StudentLab - April  6th 2017, Aula Magna, Rettorato, via Giuseppe Verdi, 8 (Turin).

"Preparing your next Professional Step" Association Bernard Gregory, ABG, Paris - April 12th 2017, Sala Multifunzione, Cavallerizza Reale, via Giuseppe Verdi, 9 (Turin). 

Workshop "Bibliography and bibliometrics like pros" - PhD students Doctoral School in Life and Health Sciences -  Teachers: Paolo Gardois, Nicoletta Colombi (Biblioteca Federata di Medicina "F. Rossi") - 5th, 9th, 12th May 2017 - Corso Dogliotti, 38 - Turin.

"D-Day 2017" Scuola di Dottorato in Scienze della Vita e della Salute -  September 19th 2017, Centro di Biotecnologie Molecolari M.B.C, Via Nizza , 52 - Turin.

2018

"CORSO DI BIOSTATISTICA 32° CICLO" - Doctoral School in Life and Health Sciences - Prof. Lorenzo Richiardi (Titolare del corso) Lecture 1: Statistical inference; Lecture 2: statistical models; Practical: Analysis of a dataset - 12-13-16 Marzo 2018, MBC, via Nizza, 52 - Torino.

"CORSO DI INGLESE SCIENTIFICO 32° CICLO" - Doctoral School in Life and Health Sciences - Prof.ssa Magdalena Sawicka (Docente esterno) - Gruppo A - MBC, via Nizza, 52 - Torino.

"D-Day 2018" Scuola di Dottorato in Scienze della Vita e della Salute - 13 Settembre 2018, Centro di Biotecnologie Molecolari M.B.C, Via Nizza , 52 - Torino

2019

"EATING DISORDERS AND SUBSTANCE ABUSE. The impact of stressful lifestyles on brain functioning" PhD in Neuroscience - University of Turin. 1st March, 2019 - Aula Magna di Anatomia - Dipartimento di Neuroscienze UNITO, Corso Massimo D’Azeglio 52.

"D-Day 2019" - September 30th 2019. Molecular Biotechnology Center, Via Nizza 52, Turin.

"Recording and stimulation techniques in Neuroscience" - March 6th,13th, 20th 27th,28th and April 3rd, 4th 2019. Corso Massimo D'Azeglio 50, Turin.

2020

"Introduction to R for Statistical Analysis" - Ugo Merlone - June 4th, 5th, 11th, 18th and 19th 2020.

 

2016

"NGF and neuro-behavioural plasticity: coping with stress in mice, rats and parachutists" Prof. Enrico Alleva, Director of the Dep. of Cellular Biology and Neuroscience - Istituto Superiore di Sanità, Roma. Associate professor of Etology at the Sapienza University of Rome. October 18th 2016,  NICO (Orbassano, Turin).

"Programming the cerebral cortex: from development to brain organoids", Arlotta Paola (Harvard University). Department of Biosciences - University of Milan - November 3rd, 2016.

"Development and reprogramming of neuronal diversity in the neocortex", Arlotta Paola (Harvard University). Via F. Sforza 28 - University of Milan - November 4th, 2016 . 

"Genetica delle disgenesie delle commissure telencefaliche", Antonio Pizzuti (Università di Roma "Sapienza"). Dip. di Scienze Mediche - University of Turin - November 15th, 2016.

"Developing molecular therapies for RETT syndrome" Stuart Cobb, PhD., Institute of Neuroscience and Psychology, College of Medical Veterinary & Life Sciences, University of Glasgow, UK. November 17th 2016, Molecular and Biotecnology Center (MBC), Turin.

"Unraveling the machanisms recognition and decision in the macaque" Prof. Piercesare Grimaldi, Department of Psychiatry and Biobehavioral Sciences - University of California, Los Angeles. December 22nd 2016, NICO (Orbassano, Turin).

2017

"Gene Regulation of Functional Brain Networks" Prof. Michele Caselle, University of Turin, Department of Physics and INFN - May 11st 2017, NICO - Regione Gonzole, 10, Orbassano, Turin.

"Neuronal signalling pathway responsiveness to temporally-encoded inputs - new insights and new tools", Prof. Michael CourtneyTurku Centre for Biotechnology, University of Turku and Åbo Academy University, Finland - May 26th 2017, NICO - Regione Gonzole, 10, Orbassano, Turin.

"Terapia Genica e Gene Editing delle cellule staminali emopoietiche per lo sviluppo di nuove terapie", May 26th 2017,  Aula Keplero MBC, Dipartimento di Biotecnologie Molecolari, Università degli Studi di Turin, via Nizza 52.

"Tumor immunoescape during glioma progression"Dr. Irene Apolloni, Laboratory of Gene Transfer - IRCCS AOU S. Martino-IST, Genova (Italy) - September 8th 2017, NICO - Regione Gonzole, 10, Orbassano, Turin.

"Structure-function relations of the hippocampal formation"Dr. Irmgard Amrein, Institute of Anatomy, University of Zurich (Switzerland) - September 12th 2017, NICO - Regione Gonzole, 10, Orbassano, Turin. 

"Novel models of stretch-induced injury in mouse oligodendrocytes and organotypic culture of cerebellar slices: study of pathophysiological mechanisms", Elena Chierto, PhD - Paris Descartes University, September 22th 2017, NICO.

"Notte europea dei ricercatori " STAND 67: Metti in gioco i tuoi neuroni. ENTE: NICO (Neuroscience Institute Cavalieri Ottolenghi) - September 29th 2017, Piazza Castello, Turin.

"On the unexpected role of SMN protein in controlling translation: implications for Spinal Muscular Atrophy", Gabriella Viero 
Institute of Biophysics, CNR Unit, Trento - October 6th 2017 - Seminars Room, NICO.

2018

"Decoding neuronal diversity of the mammalian cerebral cortex in development, evolution and disease" Simona Lodato, PhD, Dep. of Biomedical Sciences, Humanitas University- Humanitas Clinical and Research Center, IRCCS - Milan - 23 March 2018, NICO -Regione Gonzole, 10, Orbassano, Turin.

"Cortical connectivity: axonal tracing, diffusion MRI and dynamics" Prof. Giorgio M. Innocenti,Karolinska Institute, Stockholm, Sweden EPFL, Lausanne, Switzerland - 27 March 2018, NICO -Regione Gonzole, 10, Orbassano, Turin.

"From sea slugs to developing novel neurotherapeuticsSathya Puthanveettil, PhD, Department of Neuroscience - The Scripps Research Institute, Scripps Florida, USA - 10 April 2018, NICO.

"APP and Presenilins: biological function and role in neurodegenerative and neuromuscular diseases" Serena Stanga, PhD, Alzheimer Research group/CEMO, Institute of Neuroscience (IoNS) Université catholique de Louvain (UCL) - Brussels (Belgium) - 18 May 2018, NICO.

"Molecular mechanisms of motor neuron disease" Jeroen Pasterkamp, Professor of Translational Neuroscience, University Medical Center Utrecht (The Netherlands), Director MIND Facility   Chair Brain (Center Rudolf Magnus) - 29 May 2018 - NICO.

"Evolution of the amygdala (and the neural circuits for the important things)" Enrique Lanuza Universitat de València, Facultat de Ciències Biològiques Depto. de Biología Celular - 19 July 2018 - NICO.

"Vision4D - Analisi quantitativa delle immagini in 3D" workshop applicativo con:Maurizio Abbate (ARIVIS) e il Prof. Ferdinando Di Cunto (NICO - UNITO). Aula Pescetti Polo Didattico di Medicina dell'Ospedale San Luigi - 26 settembre 2018 - NICO.

"ZEISS Academy Workshop - Microscopia Correlativa 3D" Aula Pescetti Polo Didattico di Medicina dell'Ospedale San Luigi - 06/07 Novembre 2018 - NICO.

"NEURO-PORTRAITS. Imaging applications in CNS diseases." Amerigo Pagoto PostDoc, Department of Molecular Biotechnology and Health Sciences, University of Turin. Friday, 23rd November - Seminars Room, NICO.

"Meninges are a reservoir for new functional cortical neurons." Francesco Bifari, BIOMETRA - Università di Milano. Thursday, March 14th - Seminars Room, NICO.

"Monitoring Health and Disease Progression with Ultrasensitive Biomarker Analysis" Polo didattico dell’AOU San Luigi Gonzaga (Aula blu). mercoledì 10 aprile 2019, NICO.

"Early SOX9 expression in the archicortex is required for gliogenesis, granule neuron progenitor migration and dentate gyrus development." Alessia Caramello, Francis Crick Institute, London. Friday, April 19th - Seminars Room, NICO.

2019

"All in timing:effect of stress on morphology and behavior." - Dr. Prabahan Chakraborty.(National Centre for Biological Sciences, India) May 30th 2019. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO).

"How protein folding drives the onset and progression of Alzheimer's disease". - Dr. Pascal Kienlen-Campard (Universitè catholique de Louvain) May 31st 2019. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO).

"Brain Functional Shapes: How topology characterizes healthy and altered brain functions." - Dr. Giovanni Petri (ISI Foundation Turin) June 14th 2019. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO).

"Deep Learning: solutions and a problem" -Dr. Alan Perotti (ISI Foundation Turin) September 27th 2019. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO).

2020

"Healthspan vs longevity: translating research from animal models to promote healthy ageing in humans." - Dr. Francesca Cirulli. Jenuary 24th 2020. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO)

"SINEUPs: a functional class of lncRNAs that activates translation as a novel strategy for gene therapy of neurological disorders." - Dr. Stefano Espinoza. February 2nd 2020. Neuroscience Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano (TO).

"NICO NeuroWebinar" From 11th May to 31st July 2020, 1 appointment per week at 2.00 pm.  NICO-NeuroWebinar

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