|Tipo di tesi||Tesi di dottorato di ricerca|
|Autore||MORELLI, FEDERICA FRANCESCA|
|Titolo||CARATTERIZZAZIONE STRUTTURALE E FUNZIONALE DEL COMPLESSO PROTEICO HSPB2-HSPB3 E DI TRE FORME MUTATE DI HSPB3 ASSOCIATE A MALATTIE NEUROMUSCOLARI IN MODELLI CELLULARI.|
|Titolo in inglese||CHARACTERIZATION OF THE R7S MUTATION OF THE HEAT SHOCK PROTEIN HSPB3 AND OF TWO NOVEL MUTATIONS FOUND IN MYOPATHIC PATIENTS: UNDERSTANDING THE MECHANISMS LEADING TO DISEASE.|
|Settore scientifico disciplinare||BIO/11 - BIOLOGIA MOLECOLARE|
|Corso di studi||Scuola di D.R. in CLINICAL AND EXPERIMENTAL MEDICINE (CEM) - MEDICINA CLINICA E SPERIMENTALE|
|Data inizio appello||2016-02-18|
|Disponibilità||Accessibile via web (tutti i file della tesi sono accessibili)|
HSPB2 e HSPB3 sono due componenti della famiglia delle piccole proteine da shock termico, che formano un complesso proteico espresso prevalentemente nel muscolo differenziato, dove partecipano, con meccanismo non ancora conosciuto, al mantenimento muscolare.
HSPB2 and HSPB3 are component of Small Heat Shock protein family, expressed in differentiated muscle. They form a complex and participate with unknown mechanisms to muscle maintenance. The R7S mutation of HSPB3 was associated with distal hereditary motor neuropathy type 2C. Two novel mutations of HSPB3 were found in myopathic patients: a) the first one, affecting a key amino acid in the alpha-crystallin domain; b) the other one, leading to frameshift and protein truncation. We characterized basic properties of wildtype HSPB2 and HSPB3, as well as the effects of HSPB3 mutations on protein localization, stability and complex formation. One mutant of HSPB3 is degraded after synthesis, while the other mutants are stable. Among these stable mutants R7S interacts with HSPB2 while the other loses this ability. HSPB2 and HSPB3 are enriched in the nuclei, where they form intranuclear (IN) and perinuclear (PN) aggregates. Aggregation tendency of HSPB3 is increased by all mutants. Both HSPB2 and HSPB3 IN and PN aggregates alter nuclear envelope (NE) integrity and lamin A/C distribution. Lamins regulate not only nuclear shape, but also transcription. In line, HSPB2 and HSPB3 inhibit RNA transcription. Intriguingly, mutations in the LMNA gene are associated with neuromuscular disease, thereby suggesting that the nuclear effects of HSPB2/HSPB3 may be relevant to pathogenesis. Overall our data highlight a new function of the HSPB2-HSPB3 complex in the maintenance of nuclear shape and function, which is partly altered by HSPB3 mutations and may thus contribute to defects in the maintenance of the neuromuscular and muscular system observed in the patients with mutations of HSPB3. Future studies will unravel the exact function of HSPB2-HSPB3 in muscle differentiation and their exact link to disease.