Aged hind-limb clasping experimental autoimmune encephalomyelitis models aspects of the neurodegenerative process seen in multiple sclerosis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

Functional divergence of the two Elongator subcomplexes during neurodevelopment

“…The animals presented with reduced weight likely due to severe motor deficits resulting in reduced feeding ability (Cendelin, 2014). Hindlimb clasping is an indicator of lesions in the motor pathway in several mouse models of neurodegeneration (Lalonde & Strazielle, 2011;Cahill et al, 2019), including Elp2 and Elp6 mutant mice (Kojic et al, 2018(Kojic et al, , 2021, and was found to be prominent in the Elp6L118W animals as well (Fig 5B). A severe motor phenotype was consistently observed across different behavioral tests (Fig 5C).…”

Antibody targeting of aging damaged isoDGR-proteins doubles lifespan in a mouse model of chronic inflammation

“…14,39 We therefore proceeded to test the ability of isoDGR-specific immunotherapy to preserve motor and cognitive function in Pcmt1 -/- mice using clasping and ledge behaviour tests. 40–42 Six-week-old PCMT1 +/+ and Pcmt1 +/- mice displayed normal extension reflex in the hind-limbs and used body torsion when suspended in the air. In contrast, Pcmt1 -/- mice exhibited severe hind-limb clasping and high dysfunction scores than were improved upon treatment with isoDGR-specific mAb (Fig.1F).…”

Cyclin‐dependent kinase 7 contributes to myelin maintenance in the adult central nervous system and promotes myelin gene expression

“…Hindlimb clasping is a neurologic sign often found in transgenic or experimental mouse models of neurodegenerative diseases. It is associated with lesions or abnormalities in different areas of the spinal cord or the brain, and commonly due either to myelin defects or to axonal degeneration (Adebola et al, 2015; Cahill et al, 2019; De Pace et al, 2018; Scherz et al, 2018). In our study, it is unlikely that the behavior is due to axonal degeneration, as we could not observe signs of increased axonal damage or of axonal shrinkage.…”