Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice / M. Galbiati, M. Meroni, M. Boido, M. Cescon, P. Rusmini, V. Crippa, R. Cristofani, M. Piccolella, V. Ferrari, B. Tedesco, E. Casarotto, M. Chierichetti, M. Cozzi, F. Mina, M.E. Cicardi, S. Pedretti, N. Mitro, A. Caretto, P. Risè, A. Sala, A.P. Lieberman, P. Bonaldo, M. Pennuto, A. Vercelli, A. Poletti. - In: NEUROTHERAPEUTICS. - ISSN 1933-7213. - (2023), pp. 1-22. [Epub ahead of print] [10.1007/s13311-023-01343-x]

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

M. Galbiati
Primo
;
M. Meroni
Secondo
;
P. Rusmini;V. Crippa;R. Cristofani;M. Piccolella;V. Ferrari;B. Tedesco;E. Casarotto;M. Chierichetti;M. Cozzi;F. Mina;M.E. Cicardi;S. Pedretti;N. Mitro;A. Sala;A. Poletti
Ultimo
2023

Abstract

Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.
Androgen receptor; Autophagy; Motor neuron; Skeletal muscle; spinal and bulbar muscular atrophy; neurodegeneration; motor neuron diseases; HSPB8; BAG3; proteasome; motor dysfunction; aggregates; protein misfolding; testosterone
Settore BIO/13 - Biologia Applicata
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2023
30-gen-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/952808
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