Associate Professor
Downers Grove, IL
Demyelinating diseases of the central and the peripheral nervous system
I am interested in the biology of myelinating glial cells i.e. oligodendrocytes in the CNS and Schwann cells in the PNS that produce the myelin sheath, which is the lipid-rich membrane that wraps around the axons and ensures the saltatory propagation of the neuronal action potential. In demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS) and leukodystrophies i.e. the genetic disorders affecting the white matter in the CNS, as well as in demyelinating diseases of the peripheral nervous system (PNS) such as demyelinating Charcot-Marie-Tooth (CMT) diseases the myelin sheath is significantly damaged, leading to motor and sensory dysfunction causing serious neurological deficits. In my lab, we are using genetic mouse models and primary neural cell culture systems to investigate the cellular and molecular mechanisms of myelin and neuronal damage that occurs in CNS and PNS demyelinating diseases as well as to identify new molecular targets to promote myelin repair and restore neuronal function in these devastating neurological diseases.
We have developed several mouse models for CNS neurodegenerative diseases: the Aspanur7 mouse, which is an authentic model for the fatal childhood leukodystrophy Canavan disease and has helped uncover critical information regarding the pathogenesis of this disease (Traka et al., J Neurosci. 2008); the Wdr81nur5 mouse model for cerebellar ataxia, mental retardation and quadrupedal locomotion syndrome (CAMRQ2; Traka et al., J Neurosci. 2013); the diphtheria-toxin A chain (DTA) mouse model that allows for the tamoxifen-induced ablation of oligodendrocytes throughout the CNS. Our studies on the DTA mouse have revealed that the CNS has a robust innate capacity to repair myelin damage and restore neuronal function upon inducing oligodendrocyte cell loss (Traka et al., Brain 2010). Moreover, we recently used the DTA mouse to show that oligodendrocyte death might be the primary trigger of MS (Traka et al., Nat Neurosci. 2016 ; Nature Reviews Neuroscience 17, 76, 2016). This finding is of fundamental importance to our understanding of the origins of the autoimmunity that characterizes MS and it might lead to the development of new therapeutic approaches to the treatment of this devastating disease in the future.
Title
Associate Professor
Campus
Downers Grove, IL
College
Chicago College of Osteopathic Medicine
College of Dental Medicine-Illinois
College of Graduate Studies - IL
Department
Anatomy
Program
Biomedical Sciences (M.A.)
Biomedical Sciences (M.B.S.)
Dental Medicine
Optometry
Osteopathic Medicine
Physician Assistant Studies
ANATD 0520/0955 MBS/MABS Human Neurosciences (Course Director and co-Instructor)
ANATD 1511 Medical Histology (co-Instructor)
ANATD 0565 Human Neurosciences (co-Instructor)
ANATD 1521 Medical Neuroscience (co-Instructor)
IBSSD 1545 Neuroscience (co-Instructor)
IBSSD 1530 Introduction to Infectious Diseases and Integument, Soft Tissue and Lymphoreticular Systems (co-Instructor)
IBSSD 1534 Cardiovascular and Respiratory Systems (co-Instructor)
IBSSD 1540 Endocrinology/Urinary and Reproductive Systems, Growth and Aging (co-Instructor)
ANATD 0503/0945 Gross Anatomy (co-Instructor)
ANATD 1504 Gross Anatomy (co-Instructor)
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 (Figure 1).
Figure 1: Focal white matter lesions at early disease stages. (a) Focal white matter lesions (arrows) were detected in different CNS areas of the tamoxifen-treated Plp1-CreERT;ROSA26-eGFP-DTA mice ~40 weeks after injection, such as the brainstem white matter, the cerebellar white matter and the cervical spinal cord white matter. They appear as lighter areas on sections stained with hematoxylin and eosin. Insets show higher magnifications of lesions. Scale bars: 50 μm (brainstem) and 100 μm (cervical cord, cerebellum). (b,c) A focal lesion is outlined in the cerebellar white matter (dashed lines) on a toluidine blue–stained section (b). The lesion contains a high density of macrophages with lipids from degrading myelin (arrow) and myelin debris (arrowhead) in their cytoplasm, which are also shown at higher resolution by EM (c, left). A higher magnification EM image of the myelin debris is shown in c, right. EM analysis also demonstrates the presence of unmyelinated axons (ax) in the focal lesions (c, left panel). Scale bars: 10 μm (b), 2 μm (c, left) and 200 nm (c, right). (d) Focal lesions showed loss of MBP staining in the cerebellar white matter and the cervical spinal cord white matter (green, arrows), and they frequently contained T cells stained for CD3 (gray). These sites also showed increased staining for the microglia and macrophage marker CD11b (red in cervical cord, gray in cerebellum). A few unmyelinated axons were also detected in the white matter lesions by SMI31 staining (red in cerebellum, arrows). Immunofluorescence images are representative of three mice per genotype. Scale bars, 50 μm.
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 (Figure 2).
Figure 2. Aspa-deficient oligodendrocytes differentiate to mature myelinating cells that ensheath RGC axons in vitro. Retinal ganglion cell neurons (RGCs) were isolated from the retinas of postnatal day (P) 4 mice and cultured for 10-12 days before the oligodendrocyte precursor cells (OPCs) were seeded on top of the RGCs. By day 6 in the coculture, the wild-type (WT) OPCs differentiate to mature myelinating (MBP+) oligodendrocytes (~ 15% of total cells) and approximately 100% of these cells ensheath the RGC axons (SMI31+, red) forming smooth tubes of myelin around them (MBP+, green). The Aspa deficiency (ASPA KO) does not affect the capacity of the OPCs to differentiate to mature myelinating oligodendrocytes that ensheath RGC axons similarly to WT cells. N=3 cocultures per condition.
Current lab members:
Maria Traka, Ph.D. Principle Investigator
Alexander Delgado, Research Assistant
Elizabeth Markuson, CCOM-25, Research elective student, Spring 2022/Research assistant student, Summer 2022-present
Faraz Ilyas, CCOM-25, Research elective student, Spring 2022/Research assistant student, Summer 2022-present
Shreeya Sawant, CCOM-25, Research assistant student, Fall 2022-present
Lab alumni:
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
Elbaz B, Yang L, Vardy M, Isaac S, Rader BL, Kawaguchi R, Traka M, Woolf CJ, Renthal W, Popko B. Sensory neurons display cell-type-specific vulnerability to loss of neuron-glia interactions. Cell Rep. 2022 Jul 19;40(3):111130. doi: 10.1016/j.celrep.2022.111130. PubMed PMID: 35858549; PubMed Central PMCID: PMC9354470.
Traka M. The DTA Mouse Model for Oligodendrocyte Ablation and CNS Demyelination. Methods Mol Biol. 2019;1936:295-310. doi: 10.1007/978-1-4939-9072-6_17. PubMed PMID: 30820906.
Elbaz B, Traka M, Kunjamma RB, Dukala D, Brosius Lutz A, Anton ES, Barres BA, Soliven B, Popko B. Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS. Development. 2016 Jul 1;143(13):2356-66. doi: 10.1242/dev.135913. Epub 2016 May 25. PubMed PMID: 27226321; PubMed Central PMCID: PMC4958326.
Traka M, Podojil JR, McCarthy DP, Miller SD, Popko B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat Neurosci. 2016 Jan;19(1):65-74. doi: 10.1038/nn.4193. Epub 2015 Dec 14. PubMed PMID: 26656646; PubMed Central PMCID: PMC4837900.
Traka M, Millen KJ, Collins D, Elbaz B, Kidd GJ, Gomez CM, Popko B. WDR81 is necessary for purkinje and photoreceptor cell survival. J Neurosci. 2013 Apr 17;33(16):6834-44. doi: 10.1523/JNEUROSCI.2394-12.2013. PubMed PMID: 23595742; PubMed Central PMCID: PMC6618862.
Ghadge GD, Wollmann R, Baida G, Traka M, Roos RP. The L-coding region of the DA strain of Theiler's murine encephalomyelitis virus causes dysfunction and death of myelin-synthesizing cells. J Virol. 2011 Sep;85(18):9377-84. doi: 10.1128/JVI.00178-11. Epub 2011 Jul 13. PubMed PMID: 21752920; PubMed Central PMCID: PMC3165738.
Kim HJ, Miron VE, Dukala D, Proia RL, Ludwin SK, Traka M, Antel JP, Soliven B. Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. FASEB J. 2011 May;25(5):1509-18. doi: 10.1096/fj.10-173203. Epub 2011 Jan 19. PubMed PMID: 21248243; PubMed Central PMCID: PMC3079302.
Traka M, Arasi K, Avila RL, Podojil JR, Christakos A, Miller SD, Soliven B, Popko B. A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain. 2010 Oct;133(10):3017-29. doi: 10.1093/brain/awq247. Epub 2010 Sep 17. PubMed PMID: 20851998; PubMed Central PMCID: PMC4415057.
Saadat L, Dupree JL, Kilkus J, Han X, Traka M, Proia RL, Dawson G, Popko B. Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia. 2010 Mar;58(4):391-8. doi: 10.1002/glia.20930. PubMed PMID: 19705459; PubMed Central PMCID: PMC2807477.
Howng SY, Avila RL, Emery B, Traka M, Lin W, Watkins T, Cook S, Bronson R, Davisson M, Barres BA, Popko B. ZFP191 is required by oligodendrocytes for CNS myelination. Genes Dev. 2010 Feb 1;24(3):301-11. doi: 10.1101/gad.1864510. Epub 2010 Jan 15. PubMed PMID: 20080941; PubMed Central PMCID: PMC2811831.
Traka M, Wollmann RL, Cerda SR, Dugas J, Barres BA, Popko B. Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci. 2008 Nov 5;28(45):11537-49. doi: 10.1523/JNEUROSCI.1490-08.2008. PubMed PMID: 18987190; PubMed Central PMCID: PMC2613291.
Traka M, Seburn KL, Popko B. Nmf11 is a novel ENU-induced mutation in the mouse glycine receptor alpha 1 subunit. Mamm Genome. 2006 Sep;17(9):950-5. doi: 10.1007/s00335-006-0020-z. Epub 2006 Sep 8. PubMed PMID: 16964444.
Soares S, Traka M, von Boxberg Y, Bouquet C, Karagogeos D, Nothias F. Neuronal and glial expression of the adhesion molecule TAG-1 is regulated after peripheral nerve lesion or central neurodegeneration of adult nervous system. Eur J Neurosci. 2005 Mar;21(5):1169-80. doi: 10.1111/j.1460-9568.2005.03961.x. PubMed PMID: 15813926.
Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y, Fukamauchi F, Watanabe K, Soliven B, Girault JA, Karagogeos D. Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol. 2003 Sep 15;162(6):1161-72. doi: 10.1083/jcb.200305078. PubMed PMID: 12975355; PubMed Central PMCID: PMC2172849.
Traka M, Dupree JL, Popko B, Karagogeos D. The neuronal adhesion protein TAG-1 is expressed by Schwann cells and oligodendrocytes and is localized to the juxtaparanodal region of myelinated fibers. J Neurosci. 2002 Apr 15;22(8):3016-24. doi: 20026306. PubMed PMID: 11943804; PubMed Central PMCID: PMC6757518.
Chicago Chapter Society for Neuroscience (CSfN): Executive Committee Member (Secretary Elect)
Society for Neuroscience, (SfN): Member
Title: Investigating the molecular basis of Canavan disease
Agency: National Institutes of Health (NIH-1R21NS083042-01A1)
Principal Investigator: Maria Traka
Title:Development of an in vitro approach to identify molecular pathways of Canavan disease
Agency: National Tay-Sachs & Allied Diseases Association (NTSAD)
Principal Investigator: Maria Traka
Midwestern University One-Health Research Stimulus Award 2023
Midwestern University One-Health Research Stimulus Award 2019
National Institutes of Health NINDS R21 Exploratory Neuroscience Research Grant Award 2013
Myelin Repair Foundation (MRF) Award for the Best Scientific Contribution at the MRF annual meeting 2011
National Tay-Sachs & Allied Diseases Association (NTSAD) Grant Award 2010
National Multiple Sclerosis Society (NMSS) Postdoctoral Fellowship Award 2003
International Society of Neurochemistry (ISN) Fellowship 2002
