Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis – vulnerability of lower motor neurons to proximal excitotoxicity

Abstract

There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.

Non‐motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy

“…Alternatively, it is possible that both nerves and vessels respond to a neuromodulatory drive attempting to counteract disease progression . A similar phenomenon has been observed at the neuromuscular junction where terminal sprouting precedes the actual degeneration of the motor unit . In fact, in patients with more rapid disease progression rate we found higher nerve and vessel densities, interpretable as a compensatory attempt.…”

Microfluidic Models of Neuromuscular Junctions

“…Formation of grooves for the passage of axons inhibits the interruption of any unwanted experimental particle in the neuron-muscle route. 12 Blizzard et al 13 have demonstrated the use of compartmentalized microfluidic device for site-specific excitotoxin exposure. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS.…”

“…The findings of this experiment recommend that excitotoxicity in the spinal cord of individuals with ALS might result in a transneuronal degeneration , leading to permanent damage of the neurons, followed by its degeneration. 13 To study the synaptic communication among neuronal populations, Renault et al…”

Amyotrophic Lateral Sclerosis: The Current World Situation

“…Amyotrophic lateral sclerosis (ALS) is the most common form of MND, in which affected individuals generally die from respiratory failure within 2-5 years of diagnosis. [1,2] Also known as Charcot's disease (France) or Lou Gehrig's disease (USA) is a acquired disease and neurodegenerative of unknown cause that affects mainly the motor neurons of the spinal cord, brain stem and brain. [3] ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly.…”

“…The data suggest that targeted interventions, directed specifically at the cell body, might be more efficacious in tackling this devastating disease. [1] Current clinical practice for patients affected by ALS/MND includes a combination of proactive, adjunctive and symptomatic therapies. Outcome data are lacking relative to the number and variety of treatments used regularly in this population.…”