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.

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…Thus, Bace1 mutant mice and zebrafish display deficits in developmental myelination. In addition, remyelination of peripheral nerves and formation and maintenance of muscle spindles are impaired in mice, and these phenotypes resemble the well-characterized ones observed when Nrg1/ErbB signaling is ablated (Hu et al, 2006;Willem et al, 2006;Cheret et al, 2013;Fleck et al, 2013). It should be noted that phenotypes in Bace1 mutants are not as strong as the ones observed in Nrg1 signaling mutants, indicating that other proteases participate in shedding.…”

“…It should be noted that phenotypes in Bace1 mutants are not as strong as the ones observed in Nrg1 signaling mutants, indicating that other proteases participate in shedding. However, overexpression of type I Nrg1 in transgenic mice induces supernumerary muscle spindles in a strictly Bace1-dependent manner, indicating that this isoform requires Bace1 processing for its function (Cheret et al, 2013). The finding that Bace1 cleaves Nrg1 might be of interest for new therapies that are being developed for Alzheimer's disease.…”

“…Interestingly, different isoforms take over distinct functions in vivo. For instance type III and type I Nrg1 are produced by all or just a subset of sensory neurons, respectively, and have distinct functions in myelination and muscle spindle induction (Meyer and Birchmeier, 1995;Hippenmeyer et al, 2002;Perlin et al, 2011;Cheret et al, 2013). Nrg1 isoforms are produced as soluble membrane-bound proteins.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…It is worth noting, however, that, as a consequence of the unprocessed BACE1 substrate neuregulin 1, BACE1-deficient mice also show muscle spindle defects and reduced myelination of peripheral nerves, which also give rise to impaired motor coordination. 68 Thus, the contributions of cerebellar dysfunction and peripheral deficits to the motor symptoms of BACE1 ¡/¡ mice remain to be determined in future studies.…”

Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

“…Nrg1 increases terminal Schwann cells survival after postnatal denervation and promotes process extension required for new NMJ formation (Trachtenberg and Thompson, 1996;Hayworth et al, 2006). It has been also shown that Nrg1 alterations produce severe deficits in the formation and maturation of muscle spindles, thereby compromising the proprioceptive sensory system (Cheret et al, 2013). The exact role of Nrg1 type I (thereafter named Nrg1-I) on the peripheral nervous system is not fully known.…”