A transcrip+onal Approach to Myelin Repair Ben Emery Jungers Center - PowerPoint PPT Presentation

A transcrip+onal Approach to Myelin Repair Ben Emery Jungers Center for Neurosciences Research Oregon Health & Science University

MS: Causes and pathology • For any individual, the exact cause of MS is s;ll unknown, but at the popula;on level risk factors may include: Gene;cs • Infec;ons (e.g., Epstein-Barr virus) • Climate (la;tude) • Smoking • • MS involves an autoimmune aHack on myelin: From Ross et al . Front Neurol. 2013 4:21

hHp://library.med.utah.edu

Image from Klaus-Armin Nave, Max Planck Ins;tute

From www.myelin.org

From www.myelin.org

Axonal damage in MS From Trapp et al. N Engl J Med 1998; 338:278-285

Remyelina;on in MS Adams, C. W. M. A Colour Atlas of Mul.ple Sclerosis and Other Myelin Disorders (Wolfe Medical Publica;ons, London, 1989).

Remyelina;on vs. Axonal Loss Franklin and ffrench-Constant 2008. Nat Rev Neurosci. 9(11):839-55

Remyelina;on therapies in MS • Rela;vely new idea, and remyelina;on/neuroprotec;ve therapies s;ll lag behind immunomodulatory treatments • Exci;ngly, the first few clinical trials of remyelina;on treatments have been underway over past several years: An;-Lingo1 therapy (Phase 1 and 2, Biogen Idec) • Clemas;ne (Dr. Ari Green and Dr. Jonah Chan, UCSF) • rHIgM22 (Phase 1, Mayo Clinic/Acorda) • • There is a clear need for addi;onal targets for pro- remyelina;on therapies

Development of oligodendrocytes Immature/ Neural Oligodendrocyte Myelina+ng Pre-myelina+ng Precursor Progenitor (OPC) Oligodendrocyte Oligodendrocyte

Development of oligodendrocytes Immature/ Neural Oligodendrocyte Myelina+ng Pre-myelina+ng Precursor Progenitor (OPC) Oligodendrocyte Oligodendrocyte Neural Precursor Cells in developing mouse spinal cord

Development of oligodendrocytes Immature/ Neural Oligodendrocyte Myelina+ng Pre-myelina+ng Precursor Progenitor (OPC) Oligodendrocyte Oligodendrocyte Mouse OPCs in culture

Development of oligodendrocytes Immature/ Neural Oligodendrocyte Myelina+ng Pre-myelina+ng Precursor Progenitor (OPC) Oligodendrocyte Oligodendrocyte Myelin Basic Protein (MBP): young mouse brain

Development of oligodendrocytes Immature/ Neural Oligodendrocyte Myelina+ng Pre-myelina+ng Precursor Progenitor (OPC) Oligodendrocyte Oligodendrocyte Myelin Basic Protein (MBP): Developing mouse op;c nerve

Oligodendrocyte differen;a;on in MS lesions Failure of remyelina;on • As MS progresses, many demyelinated lesions fail to remyelinate • Oligodendrocytes within these regions oden “stall” in their development: Chang et al. (2002) N Eng J Med 346(3) 165-73

The fundamental ques;ons in my lab • What controls the development of oligodendrocytes? • How do oligodendrocytes and neurons communicate with each other? • How is the expression of genes regulated in oligodendrocytes?

Screen for genes with pro-myelina;on func;on in mouse development Adapted from Cahoy et al . 2008 J Neurosci 28, 264-278

Myelin Regulatory Factor An essen;ally unknown gene, now named Myelin Regulatory Factor ( Myrf ) Highly specific to oligodendrocyte lineage: Cahoy, Emery, Kaushal et al . 2008 J Neurosci 28, 264-278 Zhang, Chen, Sloan et al. 2014 J Neurosci 36, 11929-47

Myelin Regulatory Factor (Myrf): Essen;al for CNS myelina;on Control mouse: Mouse lacking Myrf: gene: Emery et al. 2009 Cell 13 8, 172-185

Forced expression of Myrf accelerates oligodendrocyte differen;a;on Control OPCs OPCs with expression of Myrf Emery et al. 2009 Cell 13 8, 172-185

How does Myrf turn on the myelina;on program?

How does the Myrf gene promote myelina;on? Myrf protein: Transmembrane Predicted domain domain For binding DNA Domain related to bacteriophages

How does the Myrf gene promote myelina;on?

Use of Myrf knockout mice as a novel model of myelin loss

Aims of our current NMSS grant • What usually turns on the expression of Myrf in oligodendrocytes (and how can we make us of this to turn it on ourselves)? • Does increased expression of Myrf in mouse models of demyelina;on improve remyelina;on? • What does Myrf look like in the brains of MS pa;ents?

Expression of Myrf in MS (with Ranjan DuHa from Cleveland Clinic) • Myrf is down-regulated in MS brains and within MS lesions • Is it expressed within “stalled” oligodendrocytes? • Is it in its ac;ve or inac;ve form? B: RNA expression of Myrf in normal appearing white maHer, ac;ve lesion border and demyelinated white maHer lesion. Data courtesy of Dr Ranjan DuOa, Cleveland Clinic.

Thanks… Emery lab Biliana Rotse AeSoon Bensen Antoinette Foster Helena Bujalka Matthias Koenning Stacey Jackson Melanie Willingham Curtis Hay Stan Mitew