Tight regulation of neurotransmitter release at synaptic connections between nerve cells is essential for maintaining stability and fidelity in the function of neural circuits. Accumulating evidence suggests that intrinsic mechanisms in neurons are at play to ensure that the amount of neurotransmitter release is adjusted efficiently and appropriately to achieve balance or homeostasis. Current experimental findings suggest that loss of homeostatic mechanisms in the nervous system may be among the earliest defects associated with age-dependent neurodegenerative disease.
The Haghighi lab investigates the molecular mechanisms that underlie synaptic homeostasis and regulate neurotransmitter release. We have discovered an important link between nutrient intake and the regulation of synaptic homeostasis, highlighting key molecular players in this process. In addition, our recent work has identified a role for a Parkinson’s-related gene in the regulation of synaptic homeostasis. Using both fly and mouse models, we are testing the hypothesis that an optimally functioning nervous system can enhance systemic healthspan and ultimately extend organismal lifespan.
Why it matters
We believe that our research program provides an alternative perspective on neurodegenerative disease, a perspective aimed at designing novel therapeutic approaches for preventing neurodegeneration rather than tackling its symptoms. In addition, through better understanding of the molecular mechanisms underlying synaptic homeostasis, we hope to pave the way for designing drugs that extend our healthspan by making neurons healthier and optimally functional.
What if neuronal dysfunction is a driver of aging, rather than a symptom of it? We are developing strategies to optimize neuronal function, thereby improving the function of all organs and extending the healthy years of life.
Pejmun Haghighi, PhD
Dr. Haghighi, a native of Iran, received his PhD from McGill University in Montreal, Canada, which was followed by a postdoctoral fellowship at the University of California, Berkeley. Dr. Haghighi was later recruited back to McGill University, where he taught and conducted research and became a tenured associate professor. He moved his laboratory to the Buck Institute in 2013.
M. C.Mario Calderon, PhD Postdoctoral Research Fellow
Dr. Calderon completed his PhD at McGill University in Montreal, Canada. He is studying the transcriptional mechanisms that underlie glia-neuron interactions and synaptic physiology.
Elie Maksoud, PhD Postdoctoral Research Fellow
Dr. Maksoud received his bachelor’s degree in biochemistry from Lebanese University in Beirut, Lebanon, and earned his master’s and PhD from Strasbourg University in Strasbourg, France. His postdoctoral work focuses on understanding the molecular mechanisms that underlie neurodegeneration induced by the Parkinson’s disease–related gene LRRK2.
Megumi Mori PhD Candidate, USC-Buck Biology of Aging Program
Megumi obtained her bachelor’s degree in neuroscience at McGill University, Montreal, Canada. She is enrolled in the USC-Buck Biology of Aging graduate program and is studying the changes in muscle proteostasis with age and the role of synaptic activity in this process.
M. M.Myriam Moujahidine Lab Manager Trainee
L. G.Lindsay Gray
E. L.Edward Liao, PhD
G. K.Grant Kauwe, PhD
- Liao, E. H., Gray, L., Tsurudome, K., El-Mounzer, W., Elazzouzi, F., Baim, C., Farzin, S., Calderon, M. R., Kauwe, G., Haghighi, A.P. (2018). Kinesin Khc-73/KIF13B modulates retrograde BMP signaling by influencing endosomal dynamics at the Drosophila neuromuscular junction. PLoS Genetics, 14(1), e1007184.
- Chong, Y., Saviuk, N., Pie, B., Basisty, N., Quinn, R., Schilling, B., Sonenberg, N., Cooper, E., Haghighi A. P. (2018). Refinement of synapses without postsynaptic activity: Role for a 4E-BP regulated mechanism. Cell Reports, 23, 11–22. DOI: 10.1016/j.celrep.2018.03.040.
- Kauwe, G., Tsurudome, K., Penney, J., Mori, M., Gray, L., Calderon, M. R., Sonenberg, N., Haghighi, A. P. (2016). Acute fasting regulates retrograde synaptic enhancement through a 4E-BP-dependent mechanism. Neuron, 92, 1204–1212.
- Penney, J., Tsurudome, K., Liao, E. H., Kauwe, G., Gray, L., Yanagiya, A., Calderon, M. R., Sonenberg, N., Haghighi, A. P. (201 July 19). LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nature Comm, 7, 12188. DOI: 10.1038/ncomms12188.
- Penney, J., Tsurudome, K., Liao, E. H., Livingstone, M., Gonzalez, M., Sonenberg, N., Haghighi, A. P. (2012 Apr 12). TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. Neuron, 74(1), 166–178.
- Tsurudome, K., Tsang, K., Liao, E. H., Yang, J. S., Elazzouzi, F., He, T., Chishti, A., Lnenicka, G., Lai, E. C., Haghighi, A. P. (2012). The Drosophila miR-310 cluster negatively regulates synaptic strength at the neuromuscular junction. Neuron, 68, 879–893.
- Ball, R. W., Warren-Paquin, M., Tsurudome, K., Liao, E., Elazzouzi, F., Cavanagh, C., An, B. S., Wang, T. T., White, J. H., Haghighi, A. P. (2012 May 27). Retrograde BMP signaling controls synaptic growth at the NMJ by regulating Trio expression in motor neurons. Neuron, 66(4), 536–49.