Modeling Myotonic Dystrophy type 2 in human cerebral organoids

PAOLA SPITALIERI

Modeling Myotonic Dystrophy type 2 in human cerebral organoids

Autori

PAOLA SPITALIERI (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)
ELISA MACRÌ (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)
FEDERICA CENTOFANTI (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)
VIRGINIA VERONICA VISCONTI (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)
MARIA GIOVANNA SCIOLI (ANATOMIC PATHOLOGY, DEPARTMENT OF BIOMEDICINE AND PREVENTION, TOR VERGATA UNIVERSITY, 00133 ROME, ITALY – ANATOMIA PATOLOGICA)
ANNALUCIA SERAFINO (INSTITUTE OF TRANSLATIONAL PHARMACOLOGY, ITALIAN NATIONAL RESEARCH COUNCIL, ROME, ITALY – )
MARZIA ROSSATO (DEPARTMENT OF BIOTECHNOLOGY, UNIVERSITY OF VERONA; 37134 VERONA, VENETO, ITALY – GENETICA UMANA)
MARCO CARLOMAGNO (DEPARTMENT OF BIOTECHNOLOGY, UNIVERSITY OF VERONA; 37134 VERONA, VENETO, ITALY – GENETICA UMANA)
ROSANNA CARDANI (BIOBANK BIOCOR, IRCCS POLICLINICO SAN DONATO, SAN DONATO MILANESE, 20097 MILAN, ITALY – BIOLOGIA CELLULARE)
GIUSEPPE NOVELLI (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY.- IRCCS NEUROMED, 86077 POZZILLI – GENETICA MEDICA)
FEDERICA SANGIUOLO (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)
ANNALISA BOTTA (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY. – GENETICA MEDICA)

Presentatore

PAOLA SPITALIERI (MEDICAL GENETICS SECTION, DEPARTMENT OF BIOMEDICINE AND PREVENTION, UNIVERSITY OF ROME TOR VERGATA, ROME, ITALY.)

Modalità

Oral Communication

Abstract

Myotonic dystrophy type 2 (DM2) is a multisystemic autosomal-dominant disorder characterized by proximal muscle weakness, myotonia, cataracts, cardiac conduction abnormalities. Although there is also clear evidence of central nervous system dysfunctions in patients, the underlying mechanism is still poorly understood. In this study, we developed 3D human cerebral organoids (hCOs) derived from DM2 induced pluripotent stem cell (hiPSC) to recapitulate the earliest stages of brain development in patients. We are able to characterize ventricular, subventricular and forebrain zones both in DM2 and control (CTR)-hCOs. Moreover, DM2-hCOs show the main disease hallmarks, including the maintenance of the CCTG expansion, the presence of CCUG-containing ribonuclear foci and the accumulation of RAN proteins. We then performed RNA-seq analysis to identify transcripts aberrantly expressed in DM2 vs. CTR-hCOs. A total of 333 genes are discovered to be differentially expressed between DM2 and CTR-hCOs, with 234 and 99 genes up and down regulated, respectively. Interestingly, among the genes strongly downregulated in DM2-hCOs we find the neuron specific transcription factors TBR1 (T-Box Brain Transcription Factor 1), TBR2 (T-Box Brain Protein 2) and FOXG1 (Forkhead Box G1). Gene Ontology and Gene Set Enrichment Analysis confirm that in DM2-hCOs several biological processes related to nervous system development, as well as to synaptic and postsynaptic transmission, are enriched. The characterization of DM2 hCOs will provide deeper insights into the molecular patho-mechanisms occurring during brain development, thus opening new perspectives for the development of cell-based therapies and drug screening not only for DM2 but also for other neurodegenerative diseases.