Disability Specific Drug Discovery in MS Focus on Vision Alessia - - PowerPoint PPT Presentation

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Apr 11, 2024 404 likes •530 views

Disability Specific Drug Discovery in MS Focus on Vision Alessia Tassoni, PhD PostDoctoral Fellow, Lab of Prof. Rhonda Voskuhl University of California, Los Angeles ActriMS, San Diego 2018 Optic neuritis in MS Frequent disability in MS

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Disability Specific Drug Discovery in MS Focus on Vision

Alessia Tassoni, PhD PostDoctoral Fellow, Lab of Prof. Rhonda Voskuhl University of California, Los Angeles ActriMS, San Diego 2018

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Optic neuritis in MS

Pathology:

Inflammation/ON Demyelination/ON RGC axonal loss/ON RGC body death/retina

Inflammatory demyelination of the optic

nerve

Frequent disability in MS

Neuroprotective therapies needed Mission: Discover neuroprotective treatments optimally tailored for visual disability in MS

Visual loss
Biomarker: OCT

RNFL thinning indicates axonal loss

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Optic neuritis in EAE: Neuroinflammationand demyelination

Iba1/MHCII GFAP/LCN2 CD45/PLP

Control 8dpi 21dpi 50dpi

8 dpi 21 dpi 50 dpi 8 dpi 21 dpi 50 dpi 8 dpi 21 dpi 50 dpi 8 dpi 21 dpi 50 dpi

MOG35-55 chronic EAE

8 dpi 21 dpi 50 dpi 8 dpi 21 dpi 50 dpi

Optic nerve Retina

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Optic neuritis in EAE: Neurodegeneration

Control 8dpi 21dpi 50dpi Optic nerve Retina

RNFL thinning by OCT RGC death and axonalloss by pathology

8 dpi 21 dpi 50 dpi 8 dpi 21 dpi 50 dpi

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Which molecule from which cell is driving visual disability progression? Ribo Tag Technology

.Sanz E, et al PNAS 2009

Discriminate gene expression changes within specific cell types in EAE optic nerve

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GFAP Cre (73.12) Ribo Tag optic nerve

HA/GFAP Colocalization Astrocytes: Key Regulators of Neuroinflammation (timing, injury, severity)

(Brambilla R,J Neuroinflam. 2012, Mayo L, Nat Med 2014, Liddelow S, Nature 2017) (Voskuhl RR, J Neuorsci 2009, Anderson MA, Burda JE et al, Nature 2016)

Beneficial Detrimental

Gfap (Astrocytes) Ptprc (Microglia) Mbp (Oligo) Gap43 (Axons)

2 4

Log2 FC (HA-IP/FT)

Cell specific enrichment & de-enrichment

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EAE Spinal cord astrocytes

RNA seq pathway analysis in optic nerve astrocytes

EAE optic nerve astrocytes

GFAP Cre RiboTag MOG35-55 chronic EAE

Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Itoh N, Itoh Y, Tassoni A PNAS, 2017

Region-specific differences in astrocytes during EAE

See Poster # 195

N. Itoh, Prof. Voskuhl

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Optic nerve astrocytes display an A1 phenotype: RNA Seq

Our data in the MS model are consistent with an important role of A1 astrocytes in the

ptic nerve crush injury model (Liddelow SA, Nature 2017)

Control EAE GFAP C3 Merge

Activation of complement during disease can be detrimental to neurons (Stephan AH, Annu Rev Neurosci. 2012)
Astrocyte defined as detrimental (A1) or beneficial (A2) (Zamanianet al. J Neurosci 2012)
Complement component 3 regarded as important upregulated A1 gene (Liddelow SA et al, Nature 2017)

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Conclusions:

RNA seq data performed on astrocyte mRNA obtained from different regions

across the CNS revealed regional differences in astrocyte specific gene expression during EAE. (PNAS 12/26/17 Epub, Jan 2018 issue. Poster #195)

In summary, our cell-specific RiboTag approach in EAE can offer therapeutically

relevant insights into molecular mechanisms underlying visual disability in MS.

In multifocal disorders such as MS, molecular mechanisms underlying each disability

may differ based on the neurological pathway involved and, therefore, neuroprotective treatments tailored for each specific disability may be required.

Molecular mechanisms of optic nerve disability progression in late EAE include

up-regulation of the complement cascade with acquisition of an A1-like phenotype.

Similar to spinal cord, optic nerve astrocytes also showed a decrease in

cholesterol synthesis gene expression in late EAE.

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Acknowledgments:

Rhonda Voskuhl

Yuichiro Itoh Noriko Itoh Roy Kim Lisa Golden Vista Farkhondeh Kevin Herrera

Michael Sofroniew

Timothy O’Shea

Funding: Thank you for the attention!

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