The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

Abstract

Summary The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington’s Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS.

Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

“…This suggests that pMad is the molecular carrier of the signaling event, purportedly transported from synaptic terminal to cell nucleus. While this model has been proposed (Bayat et al, 2011;Fuentes-Medel and Budnik, 2010), no experimental evidence supports it, and our results show that axonal transport of pMad is an unlikely mechanism for pathway relay. Similar to the situation with the BMP receptors, we find Mad in the cell body, nucleus, axon and synaptic terminal.…”

“…The authors propose that increasing BMP signaling could be a possible therapeutic approach for SMA patients. Our results describing the mechanism of BMP signaling in Drosophila motoneurons helps understand the pathological consequences of pathway disruption and will open new avenues to understand human neurodegenerative disorders that involve TGFb signaling (Bayat et al, 2011;Katsuno et al, 2010). Additionally, our results in conjunction with other reports (Bökel et al, 2006;Di Guglielmo et al, 2003) suggest that signaling endosome traffic is a general mechanism in TGF-b signaling.…”

The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

“…Furthermore, some neuromuscular disorders may be associated with perturbed BMP activity (Pescatori et al, 2007;Bayat et al, 2011). Accordingly, although our data demonstrate that increased expression of specific BMPs in muscle contributes to autocrine BMP-mediated signaling that is vital to limit catabolism in denervated muscles, it is possible that increased BMP expression by denervated muscles may also be stimulated to promote remodeling and/or regeneration of motor transcription of the endogenous inhibitory proteins Noggin and Smad6 was repressed in denervated muscles.…”

Synapse development in health and disease

“…A second synaptic growth signaling pathway is the bone morphogenetic protein (BMP) pathway, dysregulation of which is associated with multiple neurodegenerative diseases [39]. Retrograde BMP signaling at the Drosophila NMJ is initiated by release of the BMP ligand Gbb by the muscle, which triggers a signaling cascade in the presynaptic neuron [40].…”

“…The hereditary spastic paralegias (HSPs) are a group of neurological disorders caused by mutations in several genes which regulate the endosomal trafficking of BMP receptors [39,47]. Mutation of the early endosomal HSP gene NIPA1 results in less efficient sorting of the type II BMP receptor to the lysosome, suggesting that HSP etiology may involve upregulation of BMP signaling due to altered endocytic trafficking [47].…”