SBMA (or Kennedy disease) is an inherited X-linked motor neuron disease characterized by loss of lower motor neurons located in the spinal cord and brain stem. Motor neuron degeneration results in atrophy of bulbar and limb muscles. SBMA is due to an expansion of a CAG triplet repeat sequence in the androgen receptor (AR) gene, which codes for an elongated polyglutamine (polyQ) tract in the N-terminus of the AR protein. Sequence longer than 38Q are present in SBMA patients. It is known that the main cause of the disease is a gain of neurotoxic function to polyQ AR, probably correlated to aberrant conformations, leading to protein aggregation and cell toxicity. ARpolyQ toxicity is exerted only after the interaction with androgens, testosterone or its metabolite dihydrotestosterone, which induce conformational changes that release chaperones (HSP90, HSP70, etc.) complexing the receptor in the cytoplasm, and activate ARpolyQ and its nuclear translocation. In fact, several evidences show that misfolded ARpolyQ exerts most of its toxicity in the nucleus. Our hypothesis is that prevention of ARpolyQ nuclear translocation and enhancement of autophagic process could be possible approaches to counteract ARpolyQ neurotoxicity. Our in vitro results demonstrate that ARpolyQ misfolding and aggregation can be prevented by antiandrogens, like bicalutamide, an FDA-approved compound that reduces the rate of ARpolyQ nuclear translocation. The disaccharide trehalose is able to enhance ARpolyQ degradation stimulating autophagy. Furthermore, combined treatment with bicalutamide and trehalose has a potent synergic activity against ARpolyQ accumulation in neuronal models of SBMA. Utilizing a mouse model of the Kennedy disease, we show that oral trehalose treatment improves mouse motor function measured by rotarod, without affecting the hind limb muscle force. The same treatment is not able to change mouse weight or to extend their survival. Our results indicate that bicalutamide and/or trehalose could be a novel approach to counteract ARpolyQ toxicity in vitro and in vivo. It remains to be determined whether their combinatory use in mice could provide a novel valuable approach.
Trehalose and bicalutamide as therapeutic agents of Kennedy disease / M. Meroni, M.E. Cicardi, R. Cristofani, V. Crippa, V. Ferrari, E. Messi, P. Rusmini, M. Galbiati, A. Poletti. ((Intervento presentato al convegno National meeting of PhD students in neuroscience tenutosi a Napoli nel 2017.
|Titolo:||Trehalose and bicalutamide as therapeutic agents of Kennedy disease|
MERONI, MARCO (Primo)
GALBIATI, MARIARITA (Penultimo)
POLETTI, ANGELO (Ultimo)
|Data di pubblicazione:||24-feb-2017|
|Parole Chiave:||SBMA; autophagy; trehalose; bicalutamide|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
Settore BIO/13 - Biologia Applicata
|Centro di ricerca:||Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND|
Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative
|Citazione:||Trehalose and bicalutamide as therapeutic agents of Kennedy disease / M. Meroni, M.E. Cicardi, R. Cristofani, V. Crippa, V. Ferrari, E. Messi, P. Rusmini, M. Galbiati, A. Poletti. ((Intervento presentato al convegno National meeting of PhD students in neuroscience tenutosi a Napoli nel 2017.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|