Inflammatory Loss of Lower Motor Neurons in Multiple Sclerosis

Vogt J, Paul F, Aktas O, Müller-Wielsch K, Dörr J, Dörr S, Bharathi BS, Glumm R, Schmitz C, Steinbusch H, Raine CS, Tsokos M, Nitsch R, Zipp F. Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol 2009;66(3):310-22. doi: 10.1002/ana.21719. 

Background: Multiple sclerosis (MS) has long been viewed as a demyelinating disease, but increasing evidence points to neuronal degeneration as a major contributor. The distribution and mechanisms of this neuronal loss, especially within the lower motor system, were not well understood. This study examined whether such neuronal loss occurs in MS and its model, experimental autoimmune encephalomyelitis (EAE), and explored underlying immune mechanisms. 

Hypothesis: This study hypothesized that lower motor neurons are lost in MS and EAE through an inflammatory mechanism involving T lymphocytes expressing tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). 

Methods: The authors conducted electrophysiological assessments in 69 MS patients and 75 controls and quantified neurons in human spinal cord, cortex and mouse EAE tissue using high-precision design-based stereology with Stereo Investigator. Neuronal subtypes and immune cells were identified by morphology and immunostaining. 

Results: Electrophysiological data revealed reduced muscle action potentials and motor unit numbers in MS patients. Stereological analysis showed a pronounced neuronal loss – approximately 75% in the spinal cord, including 48% α-motor neuron, 81% γ-motor neuron and 67% interneuron reduction. In EAE, similar neuron loss occurred during the relapse phase and was prevented when TRAIL-deficient T cells were used, indicating TRAIL-mediated immune neurodegeneration. 

Conclusions: The study demonstrated that substantial lower motor neuron loss occurs in MS and EAE, mediated by TRAIL-expressing T cells. These findings identify inflammatory neurodegeneration of spinal motor neurons as a key contributor to MS pathology.