Developing neurons must assemble synapses of the proper size and strength to establish a functional nervous system. Disruption of synaptic growth mechanisms can result in neurodevelopmental disorders such as autism, epilepsy, and intellectual disability. While there is some understanding of the genetic aberrations that cause the development of these disorders, molecular targets for therapeutics that would ameliorate the effects of malformed synapses remain elusive. Preliminary evidence in Drosophila suggests that the MAP3K Wallenda (Wnd) is a driver of aberrant synaptic growth in larval models of neurodisorders. Previous work has shown that as a MAP3K, Wnd activates downstream MAP2Ks and MAPKs in a canonical kinase cascade to positively regulate synaptic growth. The preliminary data demonstrate that numerous upstream effector molecules are required to restrain flux through the Wnd cascade at baseline; if this level of regulation is lost, excess Wnd has the capacity to cause significant growth defects at the larval neuromuscular junction (NMJ). This proposal will employ classical genetic epistasis studies, biochemical techniques, and powerful CRIPSR- Cas9 genome engineering to test the hypothesis that hyperactive Wnd signaling drives malformed synapses in larval genetic models of neurodevelopmental disorders. Further, this project will define novel upstream molecules and mechanisms that typically restrain signaling through the Wnd pathway, thus preventing synaptic deficits in a normal nervous system. Finally, as Wnd has an evolutionarily conserved homolog in mammals called Dual Leucine Zipper Kinase (DLK), this application will explore if DLK is required for the synaptic deficits observed in mouse models of these disorders as well. This proposal aims to demonstrate that Wnd/DLK is a novel protein implicated in the dysfunctional synaptic development associated with neurodevelopmental disorders. This work has tremendous translational potential as it may provide evidence that DLK is an excellent candidate for a novel therapeutic target in the treatment of pathologies associated with human developmental disorders.
The pathologies associated with numerous neurodevelopmental disorders, including autism, epilepsy, and Down syndrome, may be attributed to improper development of synapses in the nervous system. The molecular mechanisms that cause the nervous system to develop improperly in these disorders remain elusive, hindering the development of effective therapies. This study will demonstrate that dysregulation of the MAP3K Wallenda/DLK can drive synapse malformation in fly and mouse nervous systems, potentially revealing Wallenda/DLK as a novel therapeutic target in the context of neurodevelopmental disorders.
| Karney-Grobe, Scott; Russo, Alexandra; Frey, Erin et al. (2018) HSP90 is a chaperone for DLK and is required for axon injury signaling. Proc Natl Acad Sci U S A 115:E9899-E9908 |
