VERSO UNA TERAPIA MITOCONDRIALE DELLE DISTROFIE MUSCOLARI DEL COLLAGENE VI

L'obbiettivo della ricerca

Ricercatore titolare

PAOLO BERNARDI

Partners

CECILIA GELFI

La distrofia muscolare congenita di Ullrich e la miopatia di Bethlem sono dovute alla mancanza di collagene VI, che àncora le fibre muscolari alla matrice che circonda le cellule.

Questo ha un grave effetto nelle fibre muscolari, perché causa un corto circuito nei generatori di energia della cellula, i mitocondri. Il corto circuito è dovuto all’apertura del cosiddetto poro di transizione della permeabilità (Ptp). In precedenza, abbiamo trattato con successo topi distrofici e cellule di pazienti affetti da queste forme di distrofia con la ciclosporina A (CsA), un farmaco che inibisce l’apertura di Ptp. Stiamo quindi effettuando uno studio clinico su pazienti affetti da malattie del collagene VI. I risultati sono incoraggianti, tuttavia l’uso prolungato di CsA può esporre i pazienti ai rischi dell’immunosoppressione. Per superare questo ostacolo stiamo studiando farmaci simili a CsA che non causino immunosoppressione e che siano efficaci nel trattamento del modello animale della malattia e sulle cellule dei pazienti. Inoltre, stiamo valutando l’efficacia di altri farmaci che, anziché inibire Ptp, agiscono su altre funzioni cellulari compromesse in caso di patologia. L’obiettivo è definire e convalidare un trattamento farmacologico combinatorio che possa curare le distrofie muscolari del collagene VI.

Malattie

Miopatia di Bethlem
Distrofia muscolare congenita di Ullrich

La distrofia muscolare congenita di Ullrich e la miopatia di Bethlem sono dovute alla mancanza di collagene VI, che àncora le fibre muscolari alla matrice che circonda le cellule.

Pubblicazioni scientifiche

2015 JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection
Bernardi, P; Di Lisa, FCittà: 41 (*)
2015 ACTA NEUROPATHOLOGICA
Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization
Chen, PW; Cescon, M; Zuccolotto, G; Nobbio, L; Colombelli, C; Filaferro, M; Vitale, G; Feltri, ML; Bonaldo, PCittà: 5 (*)
2014 MOLECULAR CELL
MICU1 and MICU2 Finely Tune the Mitochondrial Ca2+ Uniporter by Exerting Opposite Effects on MCU Activity
Patron, M; Checchetto, V; Raffaello, A; Teardo, E; Reane, DV; Mantoan, M; Granatiero, V; Szabo, I; De Stefani, D; Rizzuto, RCittà: 16 (*)
2014 BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Defective collagen VI a6 chain expression in the skeletal muscle of patients with collagen VI-related myopathies
Tagliavini F; Pellegrini C; Sardone F; Squarzoni S; Paulsson M; Wagener R; Gualandi F; Trabanelli C; Ferlini A; Merlini L; Santi S; Maraldi NM;Faldini C; Sabatelli PCittà: 1 (*)
2014 JOURNAL OF MOLECULAR MEDICINE-JMM
Skeletal muscle, autophagy, and physical activity: the m,nage A trois of metabolic regulation in health and disease
Vainshtein, A; Grumati, P; Sandri, M; Bonaldo, PCittà: 8 (*)
2014 ELECTROPHORESIS
Application of direct HPTLC-MALDI for the qualitative and quantitative profiling of neutral and acidic glycosphingolipids: The case of NEU3 overexpressing C2C12 murine myoblasts
Torretta, E; Vasso, M; Fania, C; Capitanio, D; Bergante, S; Piccoli, M; Tettamanti, G; Anastasia, L; Gelfi, CCittà: 1 (*)
2014 JOURNAL OF BIOLOGICAL CHEMISTRY
Regulation of the Mitochondrial Permeability Transition Pore by the Outer Membrane Does Not Involve the Peripheral Benzodiazepine Receptor ( Translocator Protein of 18 kDa ( TSPO))
Sileikyte, J; Blachly-Dyson, E; Sewell, R; Carpi, A; Menabo, R; Di Lisa, F; Ricchelli, F; Bernardi, P; Forte, MCittà: 15 (*)
2014 HUMAN MOLECULAR GENETICS
NIM811, a cyclophilin inhibitor without immunosuppressive activity, is beneficial in collagen VI congenital muscular dystrophy models
Zulian A; Rizzo E; Schiavone M; Palma E; Tagliavini F; Blaauw B; Merlini L; Maraldi NM; Sabatelli P; Braghetta P; Bonaldo P; Argenton F; Bernardi PCittà: 2 (*)
2014 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
The Oligomycin-Sensitivity Conferring Protein of Mitochondrial ATP Synthase: Emerging New Roles in Mitochondrial Pathophysiology
Antoniel, M; Giorgio, V; Fogolari, F; Glick, GD; Bernardi, P; Lippe, GCittà: 1 (*)
2014 FREE RADICAL BIOLOGY AND MEDICINE
Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies
Sorato E; Menazza S; Zulian A; Sabatelli P; Gualandi F; Merlini L; Bonaldo P; Canton M; Bernardi P; Di Lisa FCittà: 1 (*)
2014 FASEB JOURNAL
Collagen VI regulates peripheral nerve myelination and function
Chen, PW; Cescon, M; Megighian, A; Bonaldo, PCittà: 4 (*)
2014 NATURE GENETICS
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling
Logan, CV; Szabadkai, G; Sharpe, JA; Parry, DA; Torelli, S; Childs, AM; Kriek, M; Phadke, R; Johnson, CA; Roberts, NY; Bonthron, DT; Pysden, KA; Whyte, T; Munteanu, I; Foley, AR; Wheway, G; Szymanska, K; Natarajan, S; Abdelhamed, ZA; Morgan, JE; Roper, H; Santen, GWE; Niks, EH; van der Pol, WL; Lindhout, D; Raffaello, A; De Stefani, D; den Dunnen, JT; Sun, Y; Ginjaar, I; Sewry, CA; Hurles, M; Rizzuto, R; Duchen, MR; Muntoni, F; Sheridan, E; UK10K ConsortiumCittà: 19 (*)
2014 BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Extracellular matrix: A dynamic microenvironment for stem cell niche
Gattazzo, F; Urciuolo, A; Bonaldo, PCittà: 12 (*)
2014 JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY
Oxidative stress in muscular dystrophy: from generic evidence to specific sources and targets
Canton, M; Menazza, S; Di Lisa, FCittà: 2 (*)
2014 JOURNAL OF PROTEOME RESEARCH
Muscle Proteomics Reveals Novel Insights into the Pathophysiological Mechanisms of Collagen VI Myopathies
De Palma, S; Capitanio, D; Vasso, M; Braghetta, P; Scotton, C; Bonado, P; Lochmuller, H; Muntoni, F; Ferlini, A; Gelfi, CCittà: 1 (*)
2013 JOURNAL OF CELL SCIENCE
Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies
Sandri, M; Coletto, L; Grumati, P; Bonaldo, PCittà: 9 (*)
2013 FRONTIERS IN PHYSIOLOGY
The mitochondrial permeability transition pore: a mystery solved?
Bernardi, PCittà: 112 (*)
2013 BIOGERONTOLOGY
Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway
Sandri M; Barberi L; Bijlsma AY; Blaauw B; Dyar KA; Milan G; Mammucari C; Meskers CG; Pallafacchina G; Paoli A; Pion D; Roceri M; Romanello V; Serrano AL; Toniolo L; Larsson L; Maier AB; Muñoz-Cánoves P; Musarò A; Pende M; Reggiani C; Rizzuto R; Schiaffino S.Città: 21 (*)
2013 EMBO JOURNAL
The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit
Raffaello, A; De Stefani, D; Sabbadin, D; Teardo, E; Merli, G; Picard, A; Checchetto, V; Moro, S; Szabo, I; Rizzuto, RCittà: 30 (*)
2013 NATURE PROTOCOLS
Subcellular calcium measurements in mammalian cells using jellyfish photoprotein aequorin-based probes
Bonora, M; Giorgi, C; Bononi, A; Marchi, S; Patergnani, S; Rimessi, A; Rizzuto, R; Pinton, PCittà: 20 (*)
2013 CELL METABOLISM
The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase
Sciacovelli, M; Guzzo, G; Morello, V; Frezza, C; Zheng, L; Nannini, N; Calabrese, F; Laudiero, G; Esposito, F; Landriscina, M; Defilippi, P; Bernardi, P; Rasola, ACittà: 27 (*)
2013 CURRENT BIOLOGY
Downregulation of the Mitochondrial Calcium Uniporter by Cancer-Related miR-25
Marchi, S; Lupini, L; Patergnani, S; Rimessi, A; Missiroli, S; Bonora, M; Bononi, A; Corra, F; Giorgi, C; De Marchi, E; Poletti, F; Gafa, R; Lanza, G; Negrini, M; Rizzuto, R; Pinton, PCittà: 21 (*)
2013 DISEASE MODELS & MECHANISMS
Cellular and molecular mechanisms of muscle atrophy
Bonaldo, P; Sandri, MCittà: 80 (*)
2013 PLOS ONE
Changes in Muscle Cell Metabolism and Mechanotransduction Are Associated with Myopathic Phenotype in a Mouse Model of Collagen VI Deficiency
De Palma, S; Leone, R; Grumati, P; Vasso, M; Polishchuk, R; Capitanio, D; Braghetta, P; Bernardi, P; Bonaldo, P; Gelfi, CCittà: 3 (*)
2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AME
Dimers of mitochondrial ATP synthase form the permeability transition pore
Giorgio, V; von Stockum, S; Antoniel, M; Fabbro, A; Fogolari, F; Forte, M; Glick, GD; Petronilli, V; Zoratti, M; Szabo, I; Lippe, G; Bernardi, PCittà: 128 (*)
2013 PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic beta cells
Tarasov, AI; Semplici, F; Li, DL; Rizzuto, R; Ravier, MA; Gilon, P; Rutter, GACittà: 10 (*)
2013 COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY
Mitochondrial Dysfunction and Defective Autophagy in the Pathogenesis of Collagen VI Muscular Dystrophies
Bernardi, P; Bonaldo, PCittà: 5 (*)
2013 JOURNAL OF CELLULAR PHYSIOLOGY
Melanocytes-A novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy
Pellegrini, C; Zulian, A; Gualandi, F; Manzati, E; Merlini, L; Michelini, ME; Benassi, L; Marmiroli, S; Ferlini, A; Sabatelli, P; Bernardi, P; Maraldi, NMCittà: 7 (*)
2013 NATURE COMMUNICATIONS
Collagen VI regulates satellite cell self-renewal and muscle regeneration
Urciuolo, A; Quarta, M; Morbidoni, V; Gattazzo, F; Molon, S; Grumati, P; Montemurro, F; Tedesco, FS; Blaauw, B; Cossu, G; Vozzi, G; Rando, TA; Bonaldo, PCittà: 25 (*)
2012 ANTIOXIDANTS & REDOX SIGNALING
Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1(G93A) Mouse Model
Capitanio, D; Vasso, M; Ratti, A; Grignaschi, G; Volta, M; Moriggi, M; Daleno, C; Bendotti, C; Silani, V; Gelfi, CCittà: 10 (*)
2012 BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Induction of the permeability transition pore in cells depleted of mitochondrial DNA
Masgras, I; Rasola, A; Bernardi, PCittà: 9 (*)
2012 NATURE REVIEWS MOLECULAR CELL BIOLOGY
Mitochondria as sensors and regulators of calcium signalling
Rizzuto, R; De Stefani, D; Raffaello, A; Mammucari, CCittà: 147 (*)
2012 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AME
Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes
Drago, I; De Stefani, D; Rizzuto, R; Pozzan, TCittà: 27 (*)
2012 BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
The effects of idebenone on mitochondrial bioenergetics
Giorgio, V; Petronilli, V; Ghelli, A; Carelli, V; Rugolo, M; Lenaz, G; Bernardi, PCittà: 23 (*)
2012 JOURNAL OF CELLULAR PHYSIOLOGY
Critical evaluation of the use of cell cultures for inclusion in clinical trials of patients affected by collagen VI myopathies
Sabatelli, P;Palma, E;Angelin, A;Squarzoni, S;Urciuolo, A;Pellegrini, C;Tiepolo, T;Bonaldo, P;Gualandi, F;Merlini, L;Bernardi, P;Maraldi, NMCittà: 7 (*)
2012 MATRIX BIOLOGY
Expression of collagen VI a5 and a6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis
Sabatelli P; Gualandi F; Gara SK; Grumati P; Zamparelli A; Martoni E; Pellegrini C; Merlini L; Ferlini A; Bonaldo P; Maraldi NM; Paulsson M; Squarzoni S; Wagener RCittà: 11 (*)
2012 CELL DEATH AND DIFFERENTIATION
VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria
De Stefani, D; Bononi, A; Romagnoli, A; Messina, A; De Pinto, V; Pinton, P; Rizzuto, RCittà: 38 (*)
2012 HUMAN MOLECULAR GENETICS
Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation
Maltecca, F; De Stefani, D; Cassina, L; Consolato, F; Wasilewski, M; Scorrano, L; Rizzuto, R; Casari, GCittà: 10 (*)
2012 PLOS ONE
Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice
Christensen, SE; Coles, JM; Zelenski, NA; Furman, BD; Leddy, HA; Zauscher, S; Bonaldo, P; Guilak, FCittà: 8 (*)
2012 JOURNAL OF GENERAL PHYSIOLOGY
Perspectives on: SGP symposium on mitochondrial physiology and medicine: the pathophysiology of LETM1
Nowikovsky K; Pozzan T; Rizzuto R; Scorrano L; Bernardi PCittà: 17 (*)
2011 CELL CALCIUM
Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis
Rasola, A; Bernardi, PCittà: 106 (*)

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