Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis

Tanya Aggarwal, Maria J. Polanco, Chiara Scaramuzzino, Anna Rocchi, Carmelo Milioto, Laura Emionite, Emanuela Ognio, Fabio Sambataro, Mariarita Galbiati, Angelo Poletti, Maria Pennuto

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis.

Original languageEnglish
Pages (from-to)1929-1938
Number of pages10
JournalNeurobiology of Aging
Volume35
Issue number8
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • Aggregation
  • ALS
  • Androgen receptor
  • Androgens
  • Nandrolone decanoate

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology
  • Clinical Neurology

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  • Cite this

    Aggarwal, T., Polanco, M. J., Scaramuzzino, C., Rocchi, A., Milioto, C., Emionite, L., Ognio, E., Sambataro, F., Galbiati, M., Poletti, A., & Pennuto, M. (2014). Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis. Neurobiology of Aging, 35(8), 1929-1938. https://doi.org/10.1016/j.neurobiolaging.2014.02.004