Presymptomatic Neuromuscular Junction Defects and Compensatory Mechanisms in Amyotrophic Lateral Sclerosis (ALS)

The neuromuscular junction (NMJ), where the axon terminal connects the motor endplate of the muscle fiber, is the first structure affected in various Amyotrophic Lateral Sclerosis (ALS) rodent models. In these models, NMJ denervation and initial compensatory reinnervation are the earliest pathological event. These NMJ morphological defects occur far before changes can be seen at the level of motor neuron cell bodies and motor symptom onset. In these rodent models, there is thus a "latency phase" of the disease.

In ALS patients, the onset of symptoms is believed to occur when approximately 50 to 80% of motor neurons are lost and it has been suggested that the disease may have a prolonged preclinical period. After clinical onset of the disease, the existence of striking NMJ morphological defects and compensatory reinnervation of endplates has been shown in muscle of ALS patients, but their occurrence at the presymptomatic stage has never been investigated. As in animal models, at the subclinical onset of the disease, efficient reinnervation of NMJs could compensate for the loss of motor neurons and subjects would remain free of any motor symptom. As the destruction of NMJs progresses, compensation would become ineffective, leading to progressive muscle weakness and clinical onset of the disease. Identification of early, pre-symptomatic, NMJ pathological events and compensatory mechanisms could thus lead to the development of new treatment strategies to prevent motor functional impairment.

In human, the "latency phase" of the disease can be investigated in pre-manifest ALS mutation carriers. Indeed, in a population of asymptomatic carriers of C9ORF72 or SOD1 mutations (two of the main genes associated with familial ALS), a dysregulation of circulating microRNAs has been found long before the estimated time window of disease symptom onset.

The objectives of the PRE-ALS study are:

Primary objective: to investigate and characterize early, preclinical defects of NMJ morphology in muscle specimens from pre-manifest C9ORF72 or SOD1 mutation carriers;