Contribution of spinal V2 interneurons to neuromuscular integrity during the progression of Amyotrophic Lateral Sclerosis: A neurodegenerative disease

Details

Supervisors

Clotman, Frédéric

Faculty

Faculté des sciences

Degree label

Master [120] en biochimie et biologie moléculaire et cellulaire, à finalité approfondie

Abstract

enAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the progressive loss of motor neurons, leading to neuromuscular junction denervation, muscle atrophy and ultimately death, most commonly from respiratory failure. Although the disease was long considered a cell-autonomous disorder affecting motor neurons exclusively, it has become increasingly apparent that a broad range of other neuronal and non-neuronal cell types are implicated in its pathogenesis. Among these, spinal premotor interneurons, which regulate motor neuron activity through excitatory, inhibitory or neuromodulatory inputs, have emerged as potential contributors to disease progression. These premotor circuits are progressively altered during the disease, with some populations showing early loss of glycinergic inhibition and transient hyperactivity of excitatory circuits, which may contribute to motor neuron degeneration and neuromuscular decline. To date, however, the contribution of spinal V2 interneurons remains largely unexplored in the context of ALS, despite their established roles in left-right coordination and flexor-extensor contraction alternation, and in respiratory motor control. During this master’s thesis, I first developed and validated a fluorescent labelling and semi-automated analysis workflow to characterise diaphragm neuromuscular junction morphology, and applied it to a mouse model in which the ALS-associated hSOD1G37R transgene was selectively excised from V2 interneurons (V2 Preserved mice). In mice ubiquitously expressing the mutant transgene, signs of junction denervation were already detectable at symptom onset and were accompanied, from the late symptomatic stage onwards, by an increased number of shortened terminal branches, a pattern consistent with presynaptic fragmentation and terminal retraction. By contrast, V2 Preserved mice showed no measurable signs of progressive denervation until the final disease stage and maintained a relatively stable presynaptic architecture throughout disease progression. Despite originating from anatomically distinct compartments, these diaphragm findings were temporally concordant with complementary observations from the laboratory showing that significant motor neuron loss and synaptic degeneration occurred later in the lumbar spinal cord of V2 Preserved mice. Together, these results support a model in which selective preservation of V2 interneurons delays, but does not ultimately prevent, the progressive deterioration of the motor system. By sustaining premotor connectivity and delaying motor neuron degeneration, V2 preservation may contribute to the prolonged maintenance of neuromuscular junction integrity. This study therefore identifies V2 interneuron dysfunction as a contributing factor to ALS progression and potentially to the early development of neuromuscular pathology, while suggesting that it is unlikely to represent the sole initiating or driving mechanism of this multisystemic disease. Further experiments will be required to determine the extent to which V2 interneurons contribute to ALS initiation and progression.

Citations

• APA

Harte, A. (2026). Contribution of spinal V2 interneurons to neuromuscular integrity during the progression of Amyotrophic Lateral Sclerosis: A neurodegenerative disease. https://dial-mem.test.bib.ucl.ac.be/handle/2078.2/47165