Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.

Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy / Palazzolo, Isabella; Stack, Conor; Kong, Lingling; Musaro, Antonio; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Taylor, Jean Paul; Sumner, Charlotte J.; Fischbeck, Kenneth H.; Pennuto, Maria. - In: NEURON. - ISSN 0896-6273. - STAMPA. - 2009, 63:3(2009), pp. 316-328. [10.1016/j.neuron.2009.07.019]

Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.

Pennuto, Maria
2009-01-01

Abstract

Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.
2009
3
Palazzolo, Isabella; Stack, Conor; Kong, Lingling; Musaro, Antonio; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Taylor, Jean Paul; Sumner, Charlotte J.; Fischbeck, Kenneth H.; Pennuto, Maria
Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy / Palazzolo, Isabella; Stack, Conor; Kong, Lingling; Musaro, Antonio; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Taylor, Jean Paul; Sumner, Charlotte J.; Fischbeck, Kenneth H.; Pennuto, Maria. - In: NEURON. - ISSN 0896-6273. - STAMPA. - 2009, 63:3(2009), pp. 316-328. [10.1016/j.neuron.2009.07.019]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/98247
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