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

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

Jun 10, 2023 226 likes •545 views

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

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A transcrip+onal Approach to Myelin Repair

Ben Emery Jungers Center for Neurosciences Research Oregon Health & Science University

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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

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hHp://library.med.utah.edu

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

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From www.myelin.org

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From www.myelin.org

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

Axonal damage in MS

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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).

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Remyelina;on vs. Axonal Loss

Franklin and ffrench-Constant 2008. Nat Rev Neurosci. 9(11):839-55

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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

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

Development of oligodendrocytes

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

Neural Precursor Cells in developing mouse spinal cord

Development of oligodendrocytes

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

Mouse OPCs in culture

Development of oligodendrocytes

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

Myelin Basic Protein (MBP): young mouse brain

Development of oligodendrocytes

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

Myelin Basic Protein (MBP): Developing mouse op;c nerve

Development of oligodendrocytes

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Oligodendrocyte differen;a;on in MS lesions

Chang et al. (2002) N Eng J Med 346(3) 165-73

  • As MS progresses, many demyelinated lesions fail to

remyelinate

  • Oligodendrocytes within these regions oden “stall” in their

development:

Failure of remyelina;on

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The fundamental ques;ons in my lab

  • What controls the development of oligodendrocytes?
  • How do oligodendrocytes and neurons communicate with each
  • ther?
  • How is the expression of genes regulated in oligodendrocytes?
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Screen for genes with pro-myelina;on func;on in mouse development

Adapted from Cahoy et al. 2008 J Neurosci 28, 264-278

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Myelin Regulatory Factor

Cahoy, Emery, Kaushal et al. 2008 J Neurosci 28, 264-278 Zhang, Chen, Sloan et al. 2014 J Neurosci 36, 11929-47

An essen;ally unknown gene, now named Myelin Regulatory Factor (Myrf) Highly specific to oligodendrocyte lineage:

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Control mouse: Mouse lacking Myrf: gene:

Myelin Regulatory Factor (Myrf): Essen;al for CNS myelina;on

Emery et al. 2009 Cell 138, 172-185

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Forced expression of Myrf accelerates

  • ligodendrocyte differen;a;on

Emery et al. 2009 Cell 138, 172-185 Control OPCs OPCs with expression of Myrf

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How does Myrf turn on the myelina;on program?

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How does the Myrf gene promote myelina;on?

Myrf protein:

Predicted domain For binding DNA Transmembrane domain Domain related to bacteriophages

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How does the Myrf gene promote myelina;on?

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

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Aims of our current NMSS grant

  • What usually turns on the expression of Myrf in
  • ligodendrocytes (and how can we make us of this

to turn it on ourselves)?

  • Does increased expression of Myrf in mouse models
  • f demyelina;on improve remyelina;on?
  • What does Myrf look like in the brains of MS

pa;ents?

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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.

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Thanks…

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