UC San Diego

Microtubules are dynamic cytoskeletons composed of tubulins and play important roles in neuronal development, maintenance, signaling, and functions. Dysfunction of tubulins leads to the perturbation of microtubules which has been linked with many neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease, and amyotrophic lateral sclerosis. To maintain homeostasis, neurons are able to detect and respond to internal stresses through different signaling pathways. Here, I utilized a genetic model of C. elegans to investigate the neuronal responses to microtubule perturbation. The Dual Leucine zipper Kinase (DLK) is a neuronal stress-sensing MAPKKK. A gain-of-function mutation in the neuronal β-tubulin BEN-1 (BEN-1(L246F)) activates the C. elegans homolog of DLK, DLK-1, and its downstream P38 MAPK pathway. The activated DLK-1 MAPK pathway promotes the expression of the α-tubulin TBA-2, which preferentially heterodimerizes with BEN-1(L246F) to form stable regions within microtubules. This DLK-1-dependent regulation of microtubule properties protects neuron morphology, synapse formation, and synaptic vesicle trafficking from microtubule perturbation. During my master’s research, I investigated the mechanistic details of this stress-response pathway. I identified key residues in TBA-2 that facilitate its specific interaction with BEN-1(L246F). I also uncovered multiple bZIP transcription factors of the C/EBP family that likely act downstream of DLK-1 to regulate microtubule properties. Lastly, I revealed the age-dependent involvement of DLK-1 in regulating microtubule properties. Together, my findings further elucidated the DLK-1-dependent regulation of tubulin isotypes, which protects neurons from microtubule perturbation.