Rumpshaker Behaves like Juvenile-Lethal &lt;i&gt;Plp&lt;/i&gt; Mutations When Combined with Shiverer in Double Mutant Mice

The unfolded protein response (UPR) is implicated in many neurodegenerative disorders including Alzheimer, Parkinson and prion diseases, and the leukodystrophy, Pelizaeus-Merzbacher disease (PMD). Critical features of degeneration in several of these diseases involve activation of cell death pathways in various neural cell populations, and the initiator caspase 12 has been proposed to play a central role. Accordingly, pharmacological strategies to inhibit caspase 12 activity have received remarkable attention in anticipation of effecting disease amelioration. Our investigation in animal models of PMD demonstrates that caspase 12 is activated following accumulation of mutant proteins in oligodendrocytes; however, eliminating caspase 12 activity does not alter pathophysiology with respect to levels of apoptosis, oligodendrocyte function, disease severity or life span. We conclude that caspase 12 activation by UPR signaling is an epiphenomenon that plays little discernable role in the loss of oligodendrocytes in vivo and may portend the inconsequence of caspase 12 to the pathophysiology of other protein conformational diseases.

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Minimal role for caspase 12 in the unfolded protein response in oligodendrocytes in vivo

Sharma¹,

Gow

2007

“…; Billings‐Gagliardi et al . ). Inhibition of MBP synthesis by inhibition of mRNA translation in OPCs had similar effects (Bauer et al .…”

Section: The Absence Of Mbp In the Shiverer Mutant Mouse Has Effects mentioning

confidence: 97%

Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Harauz

Boggs

2013

132

170

The classic myelin basic protein (MBP) splice isoforms range in nominal molecular mass from 14 to 21.5 kDa, and arise from the gene in the oligodendrocyte lineage (Golli) in maturing oligodendrocytes. The 18.5-kDa isoform that predominates in adult myelin adheres the cytosolic surfaces of oligodendrocyte membranes together, and forms a two-dimensional molecular sieve restricting protein diffusion into compact myelin. However, this protein has additional roles including cytoskeletal assembly and membrane extension, binding to SH3-domains, participation in Fyn-mediated signaling pathways, sequestration of phosphoinositides, and maintenance of calcium homeostasis. Of the diverse post-translational modifications of this isoform, phosphorylation is the most dynamic, and modulates 18.5-kDa MBP's protein-membrane and proteinprotein interactions, indicative of a rich repertoire of functions.In developing and mature myelin, phosphorylation can result in microdomain or even nuclear targeting of the protein, supporting the conclusion that 18.5-kDa MBP has significant roles beyond membrane adhesion. The full-length, early-developmental 21.5-kDa splice isoform is predominantly karyophilic due to a non-traditional P-Y nuclear localization signal, with effects such as promotion of oligodendrocyte proliferation. We discuss in vitro and recent in vivo evidence for multifunctionality of these classic basic proteins of myelin, and argue for a systematic evaluation of the temporal and spatial distributions of these protein isoforms, and their modified variants, during oligodendrocyte differentiation. Keywords: cytoskeleton, Fyn-SH3, intrinsically disordered protein, myelin basic protein, oligodendrocyte, phosphorylation. J. Neurochem. (2013) 125, 334-361. What is myelin basic protein and what does it do?The 'classic' 18.5-kDa isoform of myelin basic protein (MBP) was first isolated more than 50 years ago as an encephalitogenic determinant (Roboz-Einstein et al. 1962;Carnegie and Lumsden 1966). This protein is an integral component of central nervous system (CNS) myelin, adhering the cytoplasmic leaflets of the oligodendrocyte (OLG) membrane to each other to form the major dense line observed in electron micrographs (Trapp and Kidd 2004). This fundamental role is demonstrated by the shiverer mutant mouse which has an ablation in the MBP gene, and whose CNS myelin is sparse and relatively unstructured (Dupouey Received December 19, 2012; revised manuscript received February 5, 2013; accepted February 5, 2013. Address correspondence and reprint requests to George Harauz, Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada. E-mail: gharauz@uoguelph.ca Abbreviations used: CaM, calmodulin; CNS, central nervous system; Golli, gene in the oligodendrocyte lineage; IDP, intrinsically disordered protein; MAPK, mitogen-activated protein kinase; MAP, microtubuleassociated protein; MBP, myelin basic protein; MoRF, molecular recognition fragment; NLS, nuclear locali...

“…These mutants exhibit myoclonus/seizures from P21, with rapidly increasing intensity correlated with depletion of the oligodendrocyte precursor pool, and rarely live beyond P30 (Skoff ; Ghandour and Skoff ; Billings‐Gagliardi et al . ). In contrast, the intensity, if not the frequency, of myoclonus in rsh mice is stable over time.…”

Section: Discussionmentioning

confidence: 97%

Dimethyl fumarate ameliorates myoclonus stemming from protein misfolding in oligodendrocytes

Southwood

Garshott

Richardson

et al. 2017

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.