title: Dimethyl fumarate ameliorates myoclonus stemming from protein misfolding in oligodendrocytes.
abstract: Multiple sclerosis (MS) is considered a primary autoimmune disease; however, this view is increasingly being challenged in basic and clinical science arenas because of the growing body of clinical trials' data showing that exclusion of immune cells from the CNS only modestly slows disease progression to disability. Accordingly, there is significant need for expanding the scope of potential disease mechanisms to understand the etiology of MS. Concomitantly, the use of a broader range of pre-clinical animal models for characterizing existing efficacious clinical treatments may elucidate additional or unexpected mechanisms of action for these drugs that augment insight into MS etiology. Herein, we explore the in vivo mechanism of action of dimethyl fumarate, which has been shown to suppress oxidative stress and immune cell responses in psoriasis and MS. Rather than studying this compound in the context of an experimental autoimmune-induced attack on the CNS, we have used a genetic model of hypomyelination, male rumpshaker (rsh) mice, which exhibit oligodendrocyte metabolic stress and startle-induced subcortical myoclonus during development and into adulthood. We find that myoclonus is reduced 30-50% in treated mutants but we do not detect substantial changes in metabolic or oxidative stress response pathways, cytokine modulation, or myelin thickness (assessed by anova). All procedures involving vertebrate animals in this study were reviewed and approved by the IACUC committee at Wayne State University.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Cherie M
authors.initials: CM
authors.lastname: Southwood
authors.affiliation: Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Garshott
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Chelsea R
authors.initials: CR
authors.lastname: Richardson
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Navid
authors.initials: N
authors.lastname: Seraji-Bozorgzad
authors.affiliation: Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fribley
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.|Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Alexander
authors.identifier: 0000-0001-7446-8990
authors.initials: A
authors.lastname: Gow
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004567:Electrodes, Implanted; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000473:pathology; D009207:Myoclonus / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000473:pathology*; D009900:Optic Nerve / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D004856:Postural Balance; D057165:Proteostasis Deficiencies / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D013216:Reflex, Startle
chemical_list: D016207:Cytokines; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D000069462:Dimethyl Fumarate
keywords: Tecfidera; leukodystrophy; neurodegeneration; neuroprotection; oxidative stress