Greg Duncan, Ph.D.

E-MAIL: [email protected]
Advising Statement

Research Interests:

Myelin is a concentric lipid-rich membrane that ensheathes the axon, ensuring that signals are transmitted quickly and efficiently throughout the nervous system. Our lab focuses on understanding the critical role of oligodendrocytes, the brain's myelin-producing cells, in maintaining neuronal health and function. When myelin is lost, as seen in the demyelinating disease multiple sclerosis (MS), it can lead to significant motor, sensory, and cognitive dysfunction.

Demyelinated neurons lose the support of oligodendrocytes, ultimately making them susceptible to damage over the long term. Neurodegeneration is the main cause of progressive disability in MS and finding strategies to diminish it is a critical unmet therapeutic need. During my postdoctoral fellowship, I identified a kinase cascade mediated by dual leucine zipper kinase (DLK) that triggers the death of chronically demyelinated neurons. Work in our laboratory builds upon this discovery to understand the specific molecular triggers driving neurodegeneration in demyelinating disease, devise new therapeutic strategies to protect neurons during demyelination, and more broadly, to understand how myelination alters neuronal function and health.

To do so, we use a variety of approaches and new technologies to interrogate how neurons are impacted by changes to, or loss of, the oligodendrocyte lineage. For example, we have developed and characterized a number of novel transgenic mouse lines that facilitate genetic control of the oligodendrocyte lineage. When combined with approaches including electron microscopy, neurophysiology, CRISPR-mediated gene editing, and single-nuclei RNAseq, we uncover mechanistic insights into how neurons become damaged by demyelination and how myelin shapes neurological function. Our current projects aim to characterize the neuronal stress response to demyelination and to elucidate how these transcriptional and metabolic changes impact neuronal vulnerability.

Clinically, our long-term hope is that this work will lead to effective therapeutic strategies that prevent neurodegeneration in MS and, in doing so, halt or slow progressive disability.

Publications

• Duncan GJ, Ingram SD, Emberley K, Hill J, Cordano C, Abdelhak A, McCane M, Jenks JE, Jabassini N, Ananth K, Ferrara SJ, Stedelin B, Sivyer B, Aicher SA, Scanlan TS, Watkins TA, Mishra A, Nelson JW, Green AJ, Emery B. Remyelination protects neurons from DLK-mediated neurodegeneration. Nat Commun. 2024 Oct 23;15(1):9148. doi: 10.1038/s41467-024-53429-5.

• Duncan GJ, Simkins TJ, Emery B. Neuron-oligodendrocyte interactions in the structure and integrity of axons. Front Cell Dev Biol. 2021 Mar 8;9:653101. doi: 10.3389/fcell.2021.653101.

• Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W. The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia. 2020 Feb;68(2):227-245. doi: 10.1002/glia.23706.

• Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Liu J, Moulson A, Plemel JR, Tetzlaff W. Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination. Nat Commun. 2018 Aug 3;9(1):3066. doi: 10.1038/s41467-018-05473-1.

• Duncan GJ, Plemel JR, Assinck P, Manesh SB, Muir FGW, Hirata R, Berson M, Liu J, Wegner M, Emery B, Moore GRW, Tetzlaff W. Myelin regulatory factor drives remyelination in multiple sclerosis.  Acta Neuropathol. 2017 Sep;134(3):403-422. doi: 10.1007/s00401-017-1741-7.

• Assinck P, Duncan GJ, Plemel JR, Lee MJ, Stratton JA, Manesh SB, Liu J, Ramer LM, Kang SH, Bergles DE, Biernaskie J, Tetzlaff W. Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury. J Neurosci. 2017 Sep 6;37(36):8635-8654. doi: 10.1523/JNEUROSCI.2409-16.2017

• Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017 Apr 25;20(5):637-647. doi: 10.1038/nn.4541.