Research in the Moulton lab focuses on delineating the molecular mechanisms of genes associated with neurological disease, especially Alzheimer’s disease. We utilize the genetic model organism, Drosophila melanogaster (fruit fly), to understand the consequences of disease-associated genetic variation. Using genetic technologies, human DNA sequences are swapped into the fly genome in place of the fly gene in order to probe the effects of specific variants on gene and organismal function (called humanization).

In the brain, proper neuronal function is supported by glial cells. When neurons experience oxidative stress (caused by neuronal activity, age, disease, etc.), they produce fatty acids, which absorb oxidative radicals and are transferred to glia where they accumulate in fat storage organelles called lipid droplets. Lipid droplets in glia can function to sequester toxic, oxidized lipids and prevent neuronal cell death and brain degeneration.

Using humanized fly models, we analyze the effects of disease-associated genetic variants on glial lipid droplet formation and neurodegeneration. Our research methods have the potential to shed light on mechanisms of complex neurological disease by aiding the identification of risk genes important for disease, determining their molecular function, modeling gene loss and variation on neurodegeneration, and identifying novel pathways for therapeutic interventions.

1. Lindsey D. Goodman*, Matthew J. Moulton*, Guang Lin, Hugo J. Bellen (2024) Does glial lipid dysregulation alters sleep in Alzheimer’s and Parkinson’s Disease? Trends in Molecular Medicine, In press; https://doi.org/10.1016/j.molmed.2024.04.010 *These authors contributed equally
2. Matthew J. Moulton, Yiming Zheng, Debdeep Dutta, Daniel Wegner, D. Katherine Grange, Wen-Wen Lin, F. Sessions Cole, Jonathan Rios, Hugo J. Bellen (2024) A Novel, Dominant, Missense Variant in SREBF2 is Associated with Dermatological and Lipid Deficit Phenotypes. Genetics in Medicine, In press; https://doi.org/10.1016/j.gim.2024.101174.
3. Lindsey D. Goodman, Isha Ralhan, Ye-Jin Park, Matthew J. Moulton, Oguz Kanca Ziyaneh S. Ghaderpour-Taleghani, Kanae Ando, Maria S. Ioannou, Hugo J. Bellen (2024) Tau is critical for glial lipid droplet formation and resistance to neuronal oxidative stress. Nature Neuroscience, In Press.
4. Isha Ralhan, Jinlan Chang, Matthew J. Moulton, Lindsey D. Goodman, Greg Plummer, H. Amalia Pasolli, Doreen Matthies, Hugo J. Bellen, Maria S. Ioannou (2023) Exocytosis of lipid-protein particles protect neurons from ferroptosis. Journal of Cell Biology 222(6):e202207130; doi: 10.1083/jcb.202207130, PMID: 37036445
5. Mengqi Ma*, Matthew J. Moulton*, Shenzhao Lu, Hugo J. Bellen (2022) ‘Fly’ing from rare to common neurodegenerative disease mechanisms. Trends in Genetics 38(9):P972–984; doi: 10.1016/ j.tig.2022.03.018, PMID: 35484057. *These authors contributed equally
6. Matthew J. Moulton, Scott Barish, Isha Ralhan, Jinlan Chang, Lindsey D. Goodman, Jake G. Harland, Paul C. Marcogliese, Jan O. Johansson, Maria S. Ioannou, Hugo J. Bellen (2021) Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease-associated genes. Proceeding of the National Academy of Sciences 118(52):e2112095118; doi: 10.1073/pnas.2112095118, PMID: 34949639
7. Lindsey D. Goodman, Heidi Cope, Zelha Nil, Thomas A. Ravenscroft, Wu-Lin Charng, Shenzhao Lu, An-Chi Tien, Rolph Pfundt, David A. Koolen, Charlotte A. Haaxma, Hermine E. Veenstra-Knol, Jolien S.Wassink-Ruiter, Marijke R. Wevers, Melissa Jones, Laurence E. Walsh, Victoria H. Klee, Miel Theunis, Eric Legius, Dora Steel, Katy E. S. Barwick, Manju A. Kurian, Shekeeb S. Mohammad, Russell C. Dale, Paulien A. Terhal, Ellen van Binsbergen, Brian Kirmse, Bethany Robinette, Benjamin Cogne, Bertrand Isidor, Theresa A. Grebe, Peggy Kulch, Bryan E. Hainline, Katherine Sapp, Eva Morava, Eric W. Klee, Erica L. Macke, Pamela Trapane, Christopher Spencer, Si Y, Begtrup A, Matthew J. Moulton, Debdeep Dutta, Oguz Kanca, UDN Consortia, Michael F. Wangler, Shinya Yamamoto, Hugo J. Bellen, Queenie K. G. Tan (2021) De novo TNPO2 variants are associated with developmental delays, neurologic deficits and dysmorphic features in humans and alter TNPO2 activity in Drosophila. American Journal of Human Genetics 108(9):1669–1691; doi: 10.1016/j.ajhg.2021.06.019, PMID: 34314705
8. Matthew J. Moulton, Alexander Kim, Gregory B. Humphreys, Anthea Letsou (2020) O-GlcNAcylation dampens Dpp/BMP signaling to ensure proper Drosophila embryonic development. Developmental Cell 53:3 330–343; doi: 10.1016/j.devcel.2020.04.001, PMID: 32369743
9. Yuanyuan Xie, Dan Kaufmann, Matthew J. Moulton, John A. Gaynes, Samin Panahi, Dingxi Zhou, Hai-Hui Xue, Camille M. Fung, Edward M. Levine, Anthea Letsou, KC Brennan, Richard I. Dorsky (2017) Lef1-dependent neurons suppress anxiety in multiple species. PLoS Biology 15(8): e2002257; doi: 10.1371/ journal.pbio.2002257, PMID: 28837622
10. Matthew J. Moulton, Anthea Letsou (2016) Modeling congenital disease and inborn errors of development in Drosophila melanogaster. Disease Models and Mechanisms 9:3 253–269; doi: 10.1242/dmm.023564, PMID: 26935104