Periodic Report Summary 1 - CORTICAL-ALS (Cortico-Spinal Motor Neurons in Amyotrophic Lateral Sclerosis : Contribution, Mechanisms and Therapy)
In the European Union, amyotrophic lateral sclerosis (ALS) affects 15 000 new individuals each year, an incidence that is similar to that of multiple sclerosis. If ALS prevalence is much lower than that of multiple sclerosis (4-8/100 000 versus 100/100 000), it is due to its extremely rapid progression of two to five years following diagnosis. These dramatic numbers portray ALS as an extremely severe and devastating disease. Unfortunately despite intensive preclinical studies, ALS remains incurable. More than ever, alternative strategies to build a better understanding of motor neuron degeneration and to propose new therapeutic approaches are needed.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 UMN degeneration in ALS, in order to design and test new therapeutic strategies based on the protection and/or the replacement of this exact neuronal type. The working hypothesis on which this project relies is that specific neurodegeneration of UMN, during the course of ALS, does not represent an isolated side effect, but rather actively contributes to the disease onset and progression.Aim 1 of the project is designed to decipher the contribution of UMN to ALS, and to directly assess whether specific UMN degeneration in ALS induces, results or is independent from that of LMN. While the question has been raised more than a century ago, it is still debated nowadays. We have designed, and are currently generating, unique mouse models that will enable us to perform selected genetic manipulations of the UMN population. A series of histological analyses and of motor behaviour tests will then be applied to understand how UMN degeneration affects LMN survival and life expectancy, and vice versa.Aim 2 of the project is intended to provide the field, for the first time, with a broad and detailed molecular picture of UMN as they degenerate in ALS. In order to do so, we have been developing a new approach to purify UMN from the cerebral cortex of healthy and ALS mice, at different stages of the disease, in order to perform gene expression analyses that will enable us, in turn, to decipher the molecular mechanisms that underlie UMN initial dysfunction and ultimate death in the context of ALS. Such data will be crucial to understand how UMN degenerate in ALS, and to design and test new therapeutic approaches towards the maintenance of UMN function and survival.The substantial lack of a cure for ALS, along with the very specific neuronal insult typical of this disease, suggest that one alternative therapeutic approach might rely on the cellular replacement of the specific neuron types that are lost in the disease. Aim 3 of the project is deigned to test a new therapeutic strategy, based on de novo and in situ generation of UMN within the diseased adult mouse brain undergoing ALS degeneration. On-going experiments will soon establish the feasibility of this new therapeutic approach.With this work, we have decided to “tackle ALS from the top”, by directly investigating the contribution of the long underestimated UMN to the disease, using new, cutting edge techniques. The work is intended not only to shed light on the contribution of UMN to ALS, but also to unravel potential new therapeutic targets that will further inform the design of new therapeutic strategies and the development of new drugs. In addition, building on our experience in the field of programming and reprogramming cellular identity in vivo, we propose to test an approach of regenerative medicine based on the generation of new UMN in the diseased mouse brain. This preclinical work holds great promise for the development of alternative therapeutic strategies, and may rapidly be translated from bench to bedside. We feel that this research program may permanently change the field of ALS research, and give rise to positive therapeutic and economic repercussions.