title: Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.
abstract: 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.
authors.affiliation: Entwicklungsbiologie/Signaltransduktion, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Cyril
authors.initials: C
authors.lastname: Cheret
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Florence R
authors.initials: FR
authors.lastname: Fricker
authors.forename: Hagen
authors.initials: H
authors.lastname: Wende
authors.forename: Annika
authors.initials: A
authors.lastname: Wulf-Goldenberg
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Alistair N
authors.initials: AN
authors.lastname: Garratt
authors.forename: David L
authors.initials: DL
authors.lastname: Bennett
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009470:Muscle Spindles / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology*; D020890:Neuregulin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011597:Psychomotor Performance / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013843:Thiazines / Q000494:pharmacology
chemical_list: C569204:LY2811376; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011480:Protease Inhibitors; D020033:Protein Isoforms; D011743:Pyrimidines; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse