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Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles

The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer’s disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among...

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Autores principales: Cheret, Cyril, Willem, Michael, Fricker, Florence R, Wende, Hagen, Wulf-Goldenberg, Annika, Tahirovic, Sabina, Nave, Klaus-Armin, Saftig, Paul, Haass, Christian, Garratt, Alistair N, Bennett, David L, Birchmeier, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Molecular Biology Organization 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715864/
https://www.ncbi.nlm.nih.gov/pubmed/23792428
http://dx.doi.org/10.1038/emboj.2013.146
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author Cheret, Cyril
Willem, Michael
Fricker, Florence R
Wende, Hagen
Wulf-Goldenberg, Annika
Tahirovic, Sabina
Nave, Klaus-Armin
Saftig, Paul
Haass, Christian
Garratt, Alistair N
Bennett, David L
Birchmeier, Carmen
author_facet Cheret, Cyril
Willem, Michael
Fricker, Florence R
Wende, Hagen
Wulf-Goldenberg, Annika
Tahirovic, Sabina
Nave, Klaus-Armin
Saftig, Paul
Haass, Christian
Garratt, Alistair N
Bennett, David L
Birchmeier, Carmen
author_sort Cheret, Cyril
collection PubMed
description The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer’s disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing β1 Nrg1 (IgNrg1β1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism.
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spelling pubmed-37158642013-07-19 Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles Cheret, Cyril Willem, Michael Fricker, Florence R Wende, Hagen Wulf-Goldenberg, Annika Tahirovic, Sabina Nave, Klaus-Armin Saftig, Paul Haass, Christian Garratt, Alistair N Bennett, David L Birchmeier, Carmen EMBO J Article The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer’s disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing β1 Nrg1 (IgNrg1β1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism. European Molecular Biology Organization 2013-07-17 2013-06-21 /pmc/articles/PMC3715864/ /pubmed/23792428 http://dx.doi.org/10.1038/emboj.2013.146 Text en Copyright © 2013, European Molecular Biology Organization https://creativecommons.org/licenses/by-nc-sa/3.0/This article is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported Licence. To view a copy of this licence visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
spellingShingle Article
Cheret, Cyril
Willem, Michael
Fricker, Florence R
Wende, Hagen
Wulf-Goldenberg, Annika
Tahirovic, Sabina
Nave, Klaus-Armin
Saftig, Paul
Haass, Christian
Garratt, Alistair N
Bennett, David L
Birchmeier, Carmen
Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title_full Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title_fullStr Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title_full_unstemmed Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title_short Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles
title_sort bace1 and neuregulin-1 cooperate to control formation and maintenance of muscle spindles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715864/
https://www.ncbi.nlm.nih.gov/pubmed/23792428
http://dx.doi.org/10.1038/emboj.2013.146
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