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

Publisher: Springer Country of Publication: United States NLM ID: 101290381 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-7479 (Electronic) Linking ISSN: 18787479 NLM ISO Abbreviation: Neurotherapeutics Subsets: MEDLINE

Publication: 2011- : New York : Springer
Original Publication: Orlando, FL : Elsevier, c2007-

Bulbo-Spinal Atrophy, X-Linked*/drug therapy ; Bulbo-Spinal Atrophy, X-Linked*/genetics ; Muscular Atrophy, Spinal*; Mice ; Animals ; Trehalose/pharmacology ; Trehalose/therapeutic use ; Receptors, Androgen/genetics ; Anilides/pharmacology ; Mice, Transgenic

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.
(© 2023. The Author(s).)

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R01 NS114007 United States NS NINDS NIH HHS

Keywords: Androgen receptor; Autophagy; Motor neuron; SBMA; Skeletal muscle

A0Z3NAU9DP (bicalutamide)
B8WCK70T7I (Trehalose)
0 (Receptors, Androgen)
0 (Anilides)

Date Created: 20230130 Date Completed: 20230425 Latest Revision: 20240204

20240205

PMC10121997

10.1007/s13311-023-01343-x

36717478