Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/emboj.2013.146

Type

Journal article

Journal

EMBO J

Publication Date

17/07/2013

Volume

32

Pages

2015 - 2028

Keywords

Alzheimer Disease, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Humans, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Muscle Spindles, Neuregulin-1, Neurogenesis, Protease Inhibitors, Protein Isoforms, Protein Processing, Post-Translational, Psychomotor Performance, Pyrimidines, Signal Transduction, Thiazines