GAIA LAURENZI

Dottoressa di ricerca

ciclo: XXXVI


supervisore: Dott.ssa Gabriella Dobrowolny

Titolo della tesi: THE ROLE OF PROTEIN-KINASE C THETA (PKCΘ) IN MUSCLE-NERVE COMMUNICATION AND IN NEUROMUSCULAR DISEASES

Neuromuscular junction (NMJ) represents the morpho-functional interface between muscle and nerve, and it is responsible for muscle contraction. Several diseases, including Amyotrophic Lateral Sclerosis (ALS) and Myasthenia Gravis (MG), are characterized by the impairment of muscle-nerve communication. Indeed, ALS is a progressive multisystemic disease, characterised by motor neurons degeneration, muscle atrophy, weakness, and progressive paralysis. Conversely, MG is an autoimmune disorder characterised by autoantibodies against NMJ components that induce muscle weakness and abnormal muscle fatigability. Interestingly, these two pathologies exhibit common features such as NMJ defects and immune cell infiltration in muscle tissue and can even rarely co-occur in the same patient. In a previous work we have characterised a transgenic mouse that over-express the human muted SOD1 gene, associated with familiar ALS, selectively in skeletal muscle (MLC/SOD1G93A mice). We observed that the muscle specific overexpression of the SOD1G93A gene was sufficient to induce NMJ dismantlement and muscle atrophy. In addition, we demonstrated a causal link between the aberrant activation of the protein kinase C θ (PKCθ) and the NMJ dismantlement. Moreover, we observed that the selective inhibition of PKCθ activity in MLC/SOD1G93A mice by compound 20 (C20) counteracted muscle atrophy ameliorating NMJ morphology and complexity. It is known that PKCθ is strictly involved in immune cell activity since it stabilizes the immunological synapse of T-cells, it is responsible for the balance between T effector and T regulatory cells and it is involved macrophagic-mediated phagocytosis. Interestingly, it has been reported that during ALS disease progression there is a gradual enrichment of macrophages nearby the NMJs and that the enhancement of their phagocytic activity is responsible for neuromuscular synapse dismantlement. The general aim of this project is to investigate the role of PKCθ in two neuromuscular disorders with different aetiopathogenesis, namely ALS and MG, both characterized by neuromuscular junction defects and alteration of muscle immune homeostasis. In addition, we want to evaluate the possibility that the inhibition of PKCθ activity could represent a therapeutical tool to counteract these diseases. During this PhD project we demonstrated that ALS and MG display common alterations in terms of muscle atrophy, muscle oxidative stress, metabolic defects and NMJ dismantlement associated with macrophages recruitment at the endplate. Moreover, we demonstrated the aberrant activation and localization of PKCθ in both ALS and MG muscles and we demonstrated that the pharmacological inhibition of PKCθ activity in murine models counteracts the ALS and MG progression attenuating muscle protein degradation, ROS accumulation, myofibers oxidative switch, NMJ dismantlement and pro-inflammatory immune infiltrate near the neuromuscular endplates. Overall our results demonstrated that (i) ALS and MG share unexpected common hallmarks, such as the aberrant activation of PKCθ; (ii) PKCθ exerts a dual role in neuromuscular endplates dismantlement and in the modulation of the immune infiltrate at the NMJ in both ALS and MG; (iii) the selective pharmacological inhibition of PKCθ activity attenuate ALS and MG clinical signs and therefore could represent a therapeutical tool to counteract these two diseases.

Produzione scientifica

11573/1718186 - 2024 - Inositol Restores Appropriate Steroidogenesis in PCOS Ovaries Both In Vitro and In Vivo Experimental Mouse Models
Fedeli, Valeria; Unfer, Vittorio; Dinicola, Simona; Simone Laganà, Antonio; Canipari, Rita; Monti, Noemi; Querqui, Alessandro; Galante, Emanuele; Laurenzi, Gaia; Bizzarri, Mariano - 01a Articolo in rivista
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. 1-19 - issn: 2073-4409 - wos: WOS:001276627200001 (0) - scopus: 2-s2.0-85199583541 (0)

11573/1705621 - 2024 - MiR206 and 423‑3p Are Differently Modulated in Fast and Slow‑Progressing Amyotrophic Lateral Sclerosis Patients
Musaro', Antonio; Dobrowolny, Gabriella; Cambieri, Chiara; Libonati, Laura; Moret, Federica; Casola, Irene; Laurenzi, Gaia; Garibaldi, Matteo; Inghilleri, Maurizio; Ceccanti, Marco - 01a Articolo in rivista
rivista: NEUROMOLECULAR MEDICINE (New York : Springer US Totowa N.J. : Humana Press, 2002-) pp. - - issn: 1559-1174 - wos: WOS:001183970300001 (0) - scopus: 2-s2.0-85187938749 (0)

11573/1692768 - 2023 - Wheel running adversely affects disease onset and neuromuscular interplay in amyotrophic lateral sclerosis slow progression mouse model
Golini, Elisabetta; Marinelli, Sara; Pisu, Simona; De Angelis, Federica; Vacca, Valentina; Rava, Alessandro; Casola, Irene; Laurenzi, Gaia; Rizzuto, Emanuele; Giuliani, Alessandro; Musarò, Antonio; Dobrowolny, Gabriella; Mandillo, Silvia - 01a Articolo in rivista
rivista: CURRENT NEUROVASCULAR RESEARCH (Hilversum: Bentham Science Publishers) pp. 362-376 - issn: 1875-5739 - wos: WOS:001079820300007 (2) - scopus: 2-s2.0-85175069414 (3)

11573/1697351 - 2023 - Decreased fertility in female mice lacking urokinase plasminogen activator
Laurenzi, Gaia; Fedeli, Valeria; Canipari, Rita - 01a Articolo in rivista
rivista: REPRODUCTIVE BIOLOGY (Olsztyn: Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences.) pp. - - issn: 1642-431X - wos: (0) - scopus: (0)

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