Abstract Details

Title CSF from MS Patients Induces Mitochondrial Dysfunction in Unmyelinated Neuronal Cultures

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 179

Objective

Background BACKGROUND: Axonal and neuronal damage are critical for permanent disability in MS patients. Oxidative stress plays a major role in axonal and neuronal injury through impairment of mitochondrial function and subsequent energy failure. Studies in human samples suggest that CSF of MS patients might modulate mitochondrial function and therefore contribute to progression of disease.

Design/Methods DESIGN/METHODS: We compared CSF from 19 MS patients and 9 controls for their ability to modulate mitochondrial function in primary cultures of unmyelinated rat hippocampal neurons with or without chronic exposure to sub-threshold levels of oxidative stress. Bioenergetic parameters were assessed using Seahorse XF24 extracellular flux analyzer (Seahorse Bioscience); mitochondrial motility studies were performed by in vivo staining with Mito Tracker (Invitrogen).

Results RESULTS: Incubation of healthy neurons with CSF from MS patients induced an altered energetic profile as measured by the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), but preserved the cellular capacity of response to stress. CSF from MS patients decreased mitochondrial motility and induced oxidative stress, shown by increased nitrotyrosine levels. In chronically-stressed neuronal cultures, CSF from MS patients induced a decrease of 30 ± 10% OCR in the cellular capacity of response to stress.

Conclusions CONCLUSIONS: This study suggests that the CSF of MS patients increases the energetic demand of healthy neurons that respond by enhancing mitochondrial function. The same CSF on chronically stressed neurons, however, induces severe impairment; these cells are unable to supply and match the increased energetic demand. These experiments support the concept of increased energetic demand in the MS brain. Future directions include large-scale proteomic study of CSF samples to identify candidate targets for neuroprotection, biomarkers for diagnosis/prognosis, and further exploration of correlations to clinical disease.

Authors/Disclosures
Ilana B. Katz Sand, MD (Corinne Goldsmith Dickinson Center for MS) PRESENTER	The institution of Dr. Katz Sand has received research support from National Multiple Sclerosis Society. The institution of Dr. Katz Sand has received research support from Hirschl Foundation. The institution of Dr. Katz Sand has received research support from National Institutes of Health. Dr. Katz Sand has received personal compensation in the range of $500-$4,999 for serving as a Conference presenter with ��ɫ��.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Sung Lee	No disclosure on file
Corey A. McGraw, MD (Upstate Medical University)	The institution of Dr. McGraw has received research support from Novartis. The institution of Dr. McGraw has received research support from F. Hoffmann - La Roche. The institution of Dr. McGraw has received research support from Genentech. The institution of Dr. McGraw has received research support from Neurona Therapeutics. The institution of Dr. McGraw has received research support from Instituto Grifols, S.A..
Angela Vidal-Jordana, MD, PhD (Hospital de la Santa Creu i Sant Pau)	No disclosure on file
Carlos A. Pardo-Villamizar, MD (Johns Hopkins U, Med Dept of Neurology)	The institution of Dr. Pardo-Villamizar has received research support from National Institutes of Health. The institution of Dr. Pardo-Villamizar has received research support from Bart McLean Fund for Neuroimmunology Research .
Peter A. Calabresi, MD, FAAN (Johns Hopkins University)	Dr. Calabresi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Calabresi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Idorsia. An immediate family member of Dr. Calabresi has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MyMD. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Myelin Repair Foundation. The institution of Dr. Calabresi has received research support from Genentech. Dr. Calabresi has received publishing royalties from a publication relating to health care. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with NIH. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Grant reveiwer with Myelin Repair Foundation. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Speaker for CME with NYAS. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Academic CME.
Fred D. Lublin, MD, FAAN (Icahn School of Medicine At Mount Sinai)	Dr. Lublin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche/Genentech. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medimmune/Viela Bio/Horizon. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Receptos/Celgene/BMS. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Labcorp. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuralight. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Entelexo. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avotres. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Lublin has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EMD Serono. Dr. Lublin has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Multiple entities. Dr. Lublin has stock in Avotres. Dr. Lublin has stock in Neuralight. The institution of Dr. Lublin has received research support from Brainstorm. The institution of Dr. Lublin has received research support from biogen. The institution of Dr. Lublin has received research support from NIH.
Aaron E. Miller, MD, FAAN (Mt Sinai School Of Med)	Dr. Miller has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Accordant Health Services (Caremark). Dr. Miller has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Corevitas (formerly known as Corrona). Dr. Miller has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MAPI=Pharma. Dr. Miller has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Viatris (Mylan). Dr. Miller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global. Dr. Miller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lehrman Group. Dr. Miller has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Idec. Dr. Miller has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Miller has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amgen (Horizon Therapeutics). Dr. Miller has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Sterne Kessler. Dr. Miller has received publishing royalties from a publication relating to health care.
	No disclosure on file
Giulio M. Pasinetti, MD, PhD (Mount Sinai School of Medicine)	No disclosure on file
Patrizia Casaccia, MD, PhD (CUNY Advanced Science Research Center)	No disclosure on file

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