Despite a large quantity of studies have been focused on the mechanisms controlling and regulating the PMP22 gene expression, the identification of new therapies for the treatment of CMT1A are still a medical need. Presently, there are no standard reliable therapies for CMT1A. Very recent preclinical (by our group) and clinical studies showed that low-dose combination of drugs, including the GABA-B receptor agonist baclofen, are efficient to improve peripheral myelination, proving also able to ameliorate a group of CMT1A patients (Chumakov et al., 2014). In the last decade, several in vitro and in vivo evidences collected in our lab demonstrated that GABA-B activation, decreases proliferation and myelin proteins expression, mainly PMPM22, playing a role in Schwann cells (SCs) differentiation. Subsequent studies on P0-CRE/GABA-B1fl/fl conditional knockout mice (specifically lacking GABA-B1 receptor in SCs) confirmed alterations in the myelination process and revealed that these mice are hyperalgesic. In these mice the morphological and behavioural changes were associated with a downregulation in NRG1 type I levels, concomitantly with an upregulation of ErbB2/ErbB3 and phosphorylated-Erk2 (pErk2), which are key regulator of SCs differentiation towards the pro-myelinating state. However, other receptors, such as the GABA-A receptors, seem to be involved in the SCs biological processes and are supposed to be cross-regulated by GABA-B. Further experiments are in progress in order elucidate the cellular and molecular mechanisms at the base of the GABA-B-mediated control of PMP22.

Are GABA-B receptor ligands of therapeutic interest for cmt1a? New insights for deciphering their mechanisms of action / V. Magnaghi. - In: JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM. - ISSN 1085-9489. - 21:3(2016 Sep), pp. 277-277. ((Intervento presentato al 6. convegno International Charcot-Marie-Tooth and related neuropathy consortium (CMTR) meeting tenutosi a Venezia-Mestre nel 2016.

Are GABA-B receptor ligands of therapeutic interest for cmt1a? New insights for deciphering their mechanisms of action

V. Magnaghi
2016-09

Abstract

Despite a large quantity of studies have been focused on the mechanisms controlling and regulating the PMP22 gene expression, the identification of new therapies for the treatment of CMT1A are still a medical need. Presently, there are no standard reliable therapies for CMT1A. Very recent preclinical (by our group) and clinical studies showed that low-dose combination of drugs, including the GABA-B receptor agonist baclofen, are efficient to improve peripheral myelination, proving also able to ameliorate a group of CMT1A patients (Chumakov et al., 2014). In the last decade, several in vitro and in vivo evidences collected in our lab demonstrated that GABA-B activation, decreases proliferation and myelin proteins expression, mainly PMPM22, playing a role in Schwann cells (SCs) differentiation. Subsequent studies on P0-CRE/GABA-B1fl/fl conditional knockout mice (specifically lacking GABA-B1 receptor in SCs) confirmed alterations in the myelination process and revealed that these mice are hyperalgesic. In these mice the morphological and behavioural changes were associated with a downregulation in NRG1 type I levels, concomitantly with an upregulation of ErbB2/ErbB3 and phosphorylated-Erk2 (pErk2), which are key regulator of SCs differentiation towards the pro-myelinating state. However, other receptors, such as the GABA-A receptors, seem to be involved in the SCs biological processes and are supposed to be cross-regulated by GABA-B. Further experiments are in progress in order elucidate the cellular and molecular mechanisms at the base of the GABA-B-mediated control of PMP22.
Settore BIO/09 - Fisiologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
Magnaghi_2016_Journal_Peripheral_Nervous_System.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 42.81 kB
Formato Adobe PDF
42.81 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/433163
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact