Search

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

Objective: The purpose of the study was to understand how people with multiple sclerosis experience dual-tasking situations in their everyday lives. Methods: Focus groups involving a total of 11 individuals with multiple sclerosis (eight females and three males) participated in this qualitative inquiry. Participants were asked open-ended questions focused on the nature of and consequences around dual tasking when standing or walking. Reflexive thematic analysis was employed to examine the data. Results: Three themes were generated from the data: (a) Life Is a Dual Task, (b) The Social Divide, and (c) Sacrifices for Stability. Conclusions: This study highlights the significance and impact of dual tasking on the lived experience of adults with multiple sclerosis, furthering the need to more fully examine this phenomenon and potentially improve fall-prevention interventions and facilitate community participation. [ABSTRACT FROM AUTHOR]

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons., Competing Interests: Competing Interests T.S.S. and B.E. are co-founders of Autobahn Therapeutics, B.E. has received consulting fees from Autobahn Therapeutics and T.S.S. is a Senior Advisor to Autobahn Therapeutics. B.E. and G.J.D. have received licensing fees for the use of Myrf inducible conditional knockout mice. These potential conflicts of interest have been reviewed and managed by OHSU.