Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

Abstract

Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.

Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing

“…Examples include "Integrin-mediated signalling", "neuron recognition", "BMP signalling pathway", "Arginine and proline metabolism", and "Lectin pathway of complement activation" (see S4 and S5 Supplementary Information). Links between some of these pathways/processes and AD and amyloid have been reported previously [28–36]. However the specific molecular mechanisms of how these processes are linked to AD have not been fully determined.…”

Target‐dependent retrograde signaling mediates synaptic plasticity at theDrosophilaneuromuscular junction

“…Retrograde Gbb acts through presynaptic BMP receptors and downstream Smad transcription factors, but after this step, the signaling pathway bifurcates. On the one hand, the activated receptors can be transported in a retrograde fashion (Smith et al, ) to activate a pool of the Mad transcription factor in the cell body (the canonical pathway; Ball et al, ; Berke et al, ; Kang et al, ; Marques et al, ; McCabe et al, ; Summerville et al, ; Zhang et al, ). Canonical BMP signaling is required for NMJ development and plasticity.…”

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

“…Only the latter proved to be effective indicating that, in the Aβ42 context, PI3K proceeds through the Medea signaling. In addition, Medea downregulation is known to attenuate BMP signaling (Wisotzkey et al, 1998) which is altered in AD (Crews et al, 2010;Kang et al, 2014). On the contrary, mTOR appears to enhance the neurotoxic effects of Aβ42 in lifespan and reduces synapse number, similarly to Aβ42 flies when expressed alone (Supp.…”