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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.

Importance: Nilotinib, a recently approved multitargeted tyrosine kinase inhibitor targeting the BCR-Abl translocation involved in chronic myelogenous leukemia, reportedly produces alopecia according to the package insert, but clinical and histologic descriptions of the alopecia are lacking. Observations: A 33-year-old woman with chronic myelogenous leukemia developed widespread alopecia involving scalp and body hair within weeks after starting nilotinib therapy. Biopsies revealed perifollicular lymphocytic inflammation and evidence of follicular injury but normal hair density, consistent with a nonscarring alopecia. Conclusions and Relevance: Nilotinib therapy may induce perifollicular inflammation and widespread persistent alopecia. We present the first clinical and histologic description of this potential adverse effect. Further investigation into the underlying mechanism of this adverse effect may produce insights into the hair growth cycle as well as potential therapeutic targets.

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