Maria Traka, Ph.D.

Project I: Mechanisms of demyelination and remyelination in adult-onset CNS demyelinating diseases
To investigate the demyelination and remyelination processes in the central nervous system (CNS), we have developed the DTA mouse model that specifically targets the ablation of mature myelin-forming oligodendrocytes by activating the expression of the diphtheria toxin A subunit (DT-A) expression in these cells through tamoxifen injections into young adult (~ 7 weeks of age) PLP/CreERT;ROSA26-eGFP-DTA (DTA) mice. The tamoxifen-treated DTA mice develop severe neurological symptoms by 5 weeks post-activation (peak of disease) that correlate with widespread oligodendrocyte loss and demyelination in the CNS (Video 1) . Strikingly, these animals fully recover from their motor and physiological defects and display extensive oligodendrocyte replenishment and widespread remyelination of the demyelinated areas by adult oligodendrocyte progenitor cells (OPCs) at approximately 10 weeks post-activation (Video 2) . Overall, the DTA mouse model shows that the CNS has a robust reparative capacity to remyelinate. Interestingly, after the tamoxifen-treated DTA mice recovered from oligodendrocyte loss, they developed a secondary, lethal disease that correlates with increased demyelination, axonal degeneration and T cell inflammation of the CNS staring at approximately 40 weeks post-activation (Video 3) . At this late-onset disease time point, focal inflammatory demyelinating lesions were found in various white matter-rich CNS areas of the tamoxifen-treated DTA mice, which progress to extensive myelin loss throughout the CNS by 1 year after injection.

Our findings suggest that primary oligodendrocyte death is sufficient to trigger an adaptive immune response against myelin suggesting that MS may develop secondary to intrinsic myelin damage ( Traka et al., Nat Neurosci. 2016 ; Highlight in Nature Reviews Neuroscience 17, 76, 2016 ). In this project, we are using the DTA mouse model to investigate the mechanisms of pathogenesis and repair in adult-onset CNS demyelinating diseases such as MS, which is the most common neurological disorder in young adults.

Project II: Mechanisms of demyelination and remyelination in adult-onset PNS demyelinating diseases

We are also using the DTA mouse model to study the impact of the Schwann cell loss in the PNS, since young adult (~ 7 weeks of age) tamoxifen-treated DTA mice show loss of the myelinating Schwann cells that leads to mild peripheral nerve demyelination causing associated neurological problems by 3 weeks post-activation and they significantly recover from their PNS defects by 10 weeks post-activation ( Benayahou Elbaz et al., Cell Reports, 2022 ). Therefore, the DTA mouse model is ideal for studying the specific effects of Schwann cell loss on myelin and axonal integrity and for dissecting the molecular pathways that are critical for the demyelination and remyelination processes in the PNS.

To investigate how aging affects the demyelination and remyelination processes in the PNS, we recently examined the impact of Schwann cell loss on myelinated fibers in sciatic nerve, as well as in auditory nerve of the mature adult (~ 6 months of age) DTA mice. Our results demonstrate that Schwann cell loss in sciatic nerves causes demyelination and associated peripheral neuropathy symptoms, such as forelimb and hindlimb weakness in these mice by 5 weeks post-activation. Furthermore, in collaboration with Dr. Ebeid's lab, we show that the density of Schwann cells within the spiral ganglion and auditory nerve in these mice is similar to controls, indicating that despite their aging, mature adult DTA mice demonstrate a robust Schwann cell regeneration in the cochleae. Additional analysis of the demyelination and remyelination processes in the PNS of the mature adult and aged (~ 9 months of age) DTA mice is currently in progress.



Project III: Role of N-Acetylaspartate (NAA) in the CNS and in Canavan disease pathogenesis.

Autosomal recessive mutations of the aspartoacylase (ASPA) gene in humans cause the fatal childhood leukodystrophy Canavan disease (CD), which involves the spongy degeneration of the CNS white matter. Affected individuals suffer from mental retardation, weakness, blindness, and functional disability, and most die by the age of five. We have identified and thoroughly characterized the N-ethyl-N-nitrosourea (ENU)-induced nonsense mutation of the mouse Aspa gene, Aspanur7 , which causes an early-onset and progressive spongy degeneration of the myelin sheath in the CNS white matter that strikingly resembles CD. ASPA has been known to catalyze the hydrolysis of the most abundant amino acid in the brain, N-acetylaspartate (NAA), to acetate and aspartic acid in mature oligodendrocytes. Although the NAA-derived acetate is being used for the myelin lipid synthesis, there is not yet a clear link between the deficient NAA hydrolysis and the myelin degeneration observed in CD. In this project, we are using genetic mouse models and myelinating co-cultures of the oligodendrocyte progenitor cells (OPCs) with the retinal ganglion cell neurons (RGCs) to investigate the role of NAA in CNS myelination and elucidating its role in CD pathogenesis, which is critical for our efforts to develop therapeutic targets that promote myelin repair in this devastating disease.

Current Lab members:

Sophia Ling, CCOM-26, Research assistant student, Summer 2023-present

Nicole Zoghby, CCOM-2026, Research assistant student, Summer 2023-present

Ailee Snapko, CCOM-2027, Research assistant student, Spring 2024-present

Payal Patel,  CCOM-2027, Research assistant student, Spring 2024-present

Lauren Hendricks, CCOM-2028, Research assistant student, Fall 2024-present

Mansi Patel, MABS-2025, Research Elective student, Winter 2024-present

Lab Alumni:

Alexander Delgado, Research Assistant

Elizabeth Markuson, CCOM-25, Research elective student, Spring 2022/Research assistant student, Summer 2022-2023

Faraz Ilyas, CCOM-25, Research elective student, Spring 2022/Research assistant student, Summer 2022-2024

Shreeya Sawant, CCOM-25, Research assistant student, Fall 2022-2024

Jessica Georgopulos, CCOM-24, Spring research elective 2021/Summer KSF student 2021/FWS student 2021-2022

Kallie Jiang, CCOM 25, FWS student 2021-2022

Shrestha Singh, CCOM-23, FWS Summer student 2020/Winter research elective 2020

Massimo Riitano, CCOM-23, Summer student 2020

Chaeyeon Kim, BioMedMA-21, Fall research elective student 2020

Sarah Yaghoubi, CCOM 23, FWS student 2019-2020

Kyle Coots, CCOM 22, Spring research elective 2019/Summer KSF student 2019

Yuliya Zayats, CCOM 22, FWS Summer student 2019
Demyelinating diseases of central and peripheral nervous system
Pathogenesis of Multiple Sclerosis and Canavan disease
Oligodendrocyte development and myelination