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Polyglutamine androgen receptor-mediated neuromuscular disease

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Abstract

An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal degeneration in spinal and bulbar muscular atrophy (SBMA), one of nine polyQ expansion diseases. Both lower motor neurons and peripheral tissues, including skeletal muscle, are affected, supporting the notion that SBMA is not a pure motor neuron disease but a degenerative disorder of the neuromuscular system. Here, we review experimental evidence demonstrating both nerve and muscle degeneration in SBMA model systems and patients. We propose that polyQ AR toxicity targets these components in a time-dependent fashion, with muscle pathology predominating early and motor neuron loss becoming more significant at late stages. This model of pathogenesis has important therapeutic implications, suggesting that symptoms arising from degeneration of nerve or muscle predominate at different points and that directed interventions targeting these components will be variably effective depending upon disease progression.

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Abbreviations

SBMA:

Spinal and bulbar muscular atrophy

CAG:

Cytosine adenine guanine

PolyQ:

Polyglutamine

AR:

Androgen receptor

T:

Testosterone

DHT:

Dihydrotestosterone

NTD:

Amino-terminal domain

DBD:

DNA-binding domain

LBD:

Ligand-binding domain

AF-1/AF-2:

Activation function

Tau-1/Tau-5:

Transcription activation unit

SRC-1:

Steroid receptor coactivator-1

NLS:

Nuclear localization signal

PEST:

Proline, glutamic acid, serine, threonine

CBP:

c-AMP responsive element binding protein

Hsp:

Heat shock proteins

CHIP:

Carboxyl terminus of Hsc70-interacting protein

N/C interaction:

Amino- and carboxy-terminus interaction

Lys:

Lysine

Ser:

Serine

SIRT1:

Sirtuin 1

IGF-1:

Insulin-like growth factor-1

CNS:

Central nervous system

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Acknowledgments

We thank Kayla Capper for help creating the illustration. Supported by the National Institutes of Health (R01 NS055746, R21 NS089516 to A.P.L.) and by the University of Michigan Protein Folding Disease Initiative.

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  1. Department of Pathology, University of Michigan Medical School, 3510 MSRB1, 1150 West Medical Center Dr., Ann Arbor, MI, USA

    Elisa Giorgetti & Andrew P. Lieberman

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  1. Elisa Giorgetti
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  2. Andrew P. Lieberman
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Correspondence to Andrew P. Lieberman.

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Giorgetti, E., Lieberman, A.P. Polyglutamine androgen receptor-mediated neuromuscular disease. Cell. Mol. Life Sci. 73, 3991–3999 (2016). https://doi.org/10.1007/s00018-016-2275-1

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