Mechanisms of neurodegeneration in Amyotrophic Lateral Sclerosis by a conserved axonal stress response signaling pathway
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that results in the death of upper and lower motoneurons, which is preceded by degeneration and loss of motoneurons axon and synaptic terminals. This project probes the molecular contributions of an evolutionarily conserved axonal stress response pathway governed by the dileucine zipper kinase DLK, which is previously known for its roles in regulating both degenerative and regenerative responses to axonal injury. Recent observations have brought new focus on DLK as a mediator of axonal loss in multiple murine models of ALS, synaptic loss in Drosophila models, and as a candidate mediator cell death in longitudinal studies of mammalian primary neurons. This project will integrate studies in these three model systems to identify downstream pathways regulated by DLK that are conserved across systems. Using ribotag technology, we will identify the DLK-regulated translatome in motoneurons isolated from mice and flies in vivo, and will functionally probe candidate downstream effectors in fly and human iPSC-derived motoneuron models. This project brings together a cross-disciplinary team towards the identification of new candidate targets in the etiology of ALS and other neurodegenerative diseases.