title: Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis.
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.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Tanya
authors.initials: T
authors.lastname: Aggarwal
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy; Dulbecco Telethon Institute Laboratory of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Polanco
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Scaramuzzino
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rocchi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy; Dulbecco Telethon Institute Laboratory of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Milioto
authors.affiliation: UOS Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la ricerca sul cancro, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.affiliation: UOS Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la ricerca sul cancro, Genoa, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ognio
authors.affiliation: Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy; Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy; Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy; Dulbecco Telethon Institute Laboratory of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: maria.pennuto@unitn.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045930:Anabolic Agents / Q000009:adverse effects; D000728:Androgens / Q000502:physiology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009277:Nandrolone / Q000009:adverse effects / Q000031:analogs & derivatives; D000077603:Nandrolone Decanoate; D009919:Orchiectomy; D011944:Receptors, Androgen / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D011944:Receptors, Androgen; C000606290:SOD1 protein, human; D009277:Nandrolone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000077603:Nandrolone Decanoate
keywords: ALS; Aggregation; Androgen receptor; Androgens; Nandrolone decanoate