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Abstract Details

Demyelinated White Matter Exhibits Upregulated DNA Damage Response and Cellular Senescence in Progressive Multiple Sclerosis
Multiple Sclerosis
P4 - Poster Session 4 (5:30 PM-6:30 PM)
9-007

To test the hypothesis that demyelination is associated with DNA damage response (DDR) and cellular senescence (CS) in progressive multiple sclerosis (P-MS).
Neurodegenerative mechanisms are thought to drive disability progression in MS. Age has been identified as the most important predictor of disability progression in MS. Recent evidence support a role of CS as a substrate of age-related neurodegeneration. The DNA damage response (DDR), a complex signal-transduction network responding to DNA lesions triggers the state of CS, which is characterized by irreversible cell-cycle arrest, a proinflammatory secretory phenotype and other changes.
Tissue blocks from post-mortem P-MS (n= 38 blocks/23 cases) and healthy controls (HC) (n=22 blocks/14 cases) were analysed. Immunohistochemistry for MOG, GFAP and HLA class II were used to detect and quantify demyelination, astrogliosis and inflammatory activity. 53BP1, a marker of DDR and GL-13 a lipofuscin detection system was used as a marker of CS in 7μm-thick sections of demyelinated white matter lesions (WML), normal appearing white matter (NAWM), normal appearing cortical gray matter (NAGM) and control white (CWM) and gray matter (CGM).

The % of 53BP1+ cells in MS WML were found increased 2.1-fold compared to NAWM and 3.8-fold compared to CWM (P< 0.01 both comparisons). The % of 53BP1+ cells correlated with GFAP (rP= 0.505, P<0.05) and HLA II immunoreactivity (rP=0.424, P<0.05) in WMLs but not in NAWM or NAGM, indicating increased DDR in demyelinated lesions, associated with astrogliosis and microglia/macrophage infiltration. The % of GL-13/lipofuscin+ cells were found increased in WMLs 1.6-fold compared to NAWM (P<0.05) and 2.6-fold compared to CWM (P<0.01), suggesting that CS may be more extensive in areas of demyelination.

Our study provides evidence of upregulated DDR and CS in demyelinated lesions in P-MS. Further work is required to eludicate how CS may contribute to the neurodegenerative processes that drive disability progression.
Authors/Disclosures
Richard S. Nicholas, FRCP (Imperial College Healthcare Trust)
PRESENTER 		Dr. Nicholas has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
Roberta Magliozzi, PhD (Dept. of Neurosciences, Biomedicine and Movement Sciences,) Dr. Magliozzi has nothing to disclose.
Dimitrios Papadopoulos, MD (European University Cyprus) No disclosure on file