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Neurobiol Aging. 2014 Aug;35(8):1929-38. doi: 10.1016/j.neurobiolaging.2014.02.004. Epub 2014 Feb 6.

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

Author information

1
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
2
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.
3
UOS Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la ricerca sul cancro, Genoa, Italy.
4
Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto, Italy.
5
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.
6
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.

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.

KEYWORDS:

ALS; Aggregation; Androgen receptor; Androgens; Nandrolone decanoate

[Indexed for MEDLINE]

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