Abstract Details

Title Metabolic Stress Induces the Mislocalization of RNA Binding Protein TDP-43 in Human Oligodendrocytes in Vitro

Topic Multiple Sclerosis

Presentation(s) P3 - Poster Session 3 (12:00 PM-1:00 PM)

Poster/Presentation
Number 9-019

Objective Determine whether metabolic stress (low glucose (LG)/reduced nutrients) induces mislocalization of RBP TDP-43 in human OLs (hOLs) and rat OL progenitor (rOPCs) and its relation to cell injury responses.

Background Decreased nuclear expression of TDP-43, an RNA-binding protein (RBP) that is predominantly localized in the nucleus, impairs myelination and reduces cell survival in rodent oligodendrocytes (OLs) (Wang et al., 2018). Metabolic stress is an implicated contributor to OL injury in multiple sclerosis lesions.

Design/Methods Dissociated cultures of hOLs from adult surgical resections and rOPCs from post-natal brains were maintained in optimal culture conditions (N1) or LG conditions for 24-48 hours. Cell survival /death was assessed by propidium iodide (PI) staining. Localization of TDP-43 was assessed by immunofluorescence.

Results

After 48 hours in LG conditions, hOLs show only a marginal increase in cell death compared to N1 conditions. However, ongoing sublethal injury could be documented by retraction of cell processes. Under LG conditions, hOLs show a higher % of nuclear depletion of TDP-43 compared to control (mean 46±8% for LG vs 17±9 % for N1, p<0.05, n=4 for total cells; 44±8% for LG vs 14±9% for N1, p<0.05, n=3, if only PI negative cells are included). All PI+ cells had TDP-43 nuclear depletion. Similar findings were observed in rOPCs when examined at 24 hours. Mislocalized TDP-43 was diffusely distributed in the cytoplasm of hOLs and rOPCs with no TDP-43 aggregates.

Conclusions

Metabolic stress conditions can induce mislocalization of RBP TDP-43 with the latter occurring when cell insults are still sub-lethal and potentially reversible. Continued insults lead to lethal injury with universal nuclear depletion of TDP-43. The relation between progressive injury and TDP-43 accumulation remains to be established.

Authors/Disclosures
PRESENTER	No disclosure on file
Qiao Ling Cui, MD	No disclosure on file
Katsuhisa Masaki, MD (Kyushu university)	No disclosure on file
Raymond P. Roos, MD, FAAN (University of Chicago Med Ctr)	Dr. Roos has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for MedLink. Dr. Roos has stock in Amazon. Dr. Roos has stock in Amgen. Dr. Roos has stock in Apple. Dr. Roos has stock in Cigna. Dr. Roos has stock in IBM. Dr. Roos has stock in Ionis. Dr. Roos has stock in Pfizer. Dr. Roos has received research support from Lohengrin Foundation.
Jack P. Antel, MD, FAAN (Montreal Neurologic Hospital)	Dr. Antel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for sanofi, roche, biogen, wave,nervgen. The institution of Dr. Antel has received research support from Novartis canada bristol myers squib. Dr. Antel has a non-compensated relationship as a past president with ACTRIMS that is relevant to AAN interests or activities.

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