Upper Motor Neurons and Amyotrophic Lateral Sclerosis: Contribution, Mechanisms and Therapy – CorticALS

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset neurodegenerative disease of the motor system, with a prevalence of 2-3/100 000. In spite of intensive research efforts, ALS remains an incurable disease and presents with a very severe prognosis, leading to patient death, usually due to respiratory failure, within 2 to 5 years following diagnosis.

At the cellular level, ALS is characterized by the combined degeneration of both upper motor neurons (UMN, or corticospinal motor neurons), whose cell bodies are located in the cerebral cortex, and that extend axons to the medulla and spinal cord, and lower motor neurons (LMN, or spinal motor neurons), whose cell bodies are located in the medulla and spinal cord, and that connect to the skeletal muscles. This dual impairment allows discriminating ALS from other, less severe diseases affecting either the UMN only (e.g. hereditary spastic paraplegia, primary lateral sclerosis), or the LMN only (e.g. progressive muscular atrophy, spinobulbar muscular atrophy or Kennedy’s disease, spinomuscular atrophy). Despite this precise clinical description, it is striking to note that preclinical studies have so far mostly concentrated on LMN, leaving aside the role of UMN in ALS. The main reason for this seeming disinterest for UMN may arise from the extraordinary cellular complexity of the cerebral cortex where UMN cell bodies are located. However, recent advances in the field of cortical development have provided scientists with a molecular toolbox that allows now for the identification of individual neuronal sub-populations enabling their specific study, not only during corticogenesis, but also under pathological conditions.

This project aims at shedding light on the contribution of the dysfunction and/or the loss of UMN in ALS, in order to design and test new therapeutic strategies based on the protection and/or the replacement of this exact neuronal type. This innovative question has never been directly asked so far. The working hypothesis on which this project relies is that specific neurodegeneration of UMN, in the course of ALS, does not represent an isolated side effect of the disease, but rather actively contributes to its onset and progression.

In order to decipher the contribution of UMN to ALS, we will first determine their role on the onset and progression of the disease, and establish whether specific UMN degeneration in ALS induces, results or is independent from that of LMN. In parallel, we will unravel the molecular mechanisms that control the selective dysfunction and ultimate death of UMN during the course of ALS. Finally, we will test a first therapeutic strategy, based on de novo and in situ generation of UMN within the diseased adult mouse brain undergoing ALS degeneration.

Above ALS, this proposal aims at contributing to the research efforts conducted on neurodegenerative diseases that affect the motor system. Based on the discovery of new molecular players, and the development of alternative therapeutic strategies, this original program has the ambition to provide clinicians and patients with new answers and new therapeutic assets.