ABSTRACT
Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.
ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the progression of ALS. Single-cell mass cytometry (CyTOF) analysis revealed prominent expression of α5 integrin in microglia and macrophages in a superoxide dismutase-1 G93A mouse model of ALS (SOD1G93A). In postmortem tissues from ALS patients with various clinical ALS phenotypes and disease duration, α5 integrin is prominent in motor pathways of the central and peripheral nervous system and in perivascular zones associated with the blood-brain barrier. In SOD1G93A mice, administration of a monoclonal antibody against α5 integrin increased survival compared to an isotype control and improved motor function on behavioral testing. Together, these findings in mice and in humans suggest that α5 integrin is a potential therapeutic target in ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Motor Cortex , Mice , Humans , Animals , Amyotrophic Lateral Sclerosis/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Integrin alpha5/metabolism , Mice, Transgenic , Superoxide Dismutase/metabolism , Macrophages/metabolism , Disease Models, AnimalABSTRACT
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.
