Caroline RouauxInserm U 1118, Université de Strasbourg, France
Evaluation of the corticofugal hypothesis in ALS, by Caroline Rouaux
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Summary of the seminar:
Amyotrophic lateral sclerosis (ALS) is the third most frequent neurodegenerative disease after Alzheimer’s and Parkinson’s diseases, and the most frequent disease of the adult motoneuron. Clinically and histopathologically, ALS is defined as the simultaneous degeneration of corticospinal neurons (CSN) in the motor cortex, and bulbar and spinal motor neurons (MN), leading to muscle denervation, rapidly progressing paralysis and death. While preclinical studies have greatly contributed to our understanding of the mechanisms that govern MN degeneration, little is known about the contribution of the motor cortex, the CSN and other populations of cortical neurons and glia to MN survival and more broadly to disease onset and progression.
Recent clinical and pathological studies suggest that ALS might start in the motor cortex and spread along the corticofugal axonal projections (including the CSN), according to the so-called corticofugal hypothesis of ALS. Two mechanisms have been proposed i) altered cortical excitability and subsequent excitotoxicity, or ii) prion-like propagation of misfolded proteins. Using various mouse models of the disease and combination of behavioural, functional and molecular approaches, we are testing the corticofugal hypothesis of ALS in order to identify i) the type and kinetics of cortical impairments, ii) the contribution of corticofual populations to disease onset and progression, and iii) the type of detrimental message conveyed by the motor cortex to its targets. The long term goal of this research project is to determine whether the motor cortex and its cellular populations could represent new therapeutic targets and design innovative treatment strategies to combat ALS.
Short Biography of Caroline Rouaux:
Caroline Rouaux’s preclinical research is dedicated to neurodegeneration and regeneration related to Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease that targets neurons involved in voluntary motor control (motoneurons and corticospinal neurons) and leads to quickly progressing paralysis and death. During her PhD in Strasbourg, she described the impact of altered epigenetic regulations on the survival of motor neuron in ALS, and tested therapeutic strategies aimed at restoring their epigenetic status [Rouaux et al., EMBO J, 2003; Rouaux et al., J Neurosci, 2007]. This early work highlighted the discrepancy between spinal motor neuron survival and disease onset and progression, and prompted her to seek for other contributors. She then joined the Arlotta lab at Harvard University to study the corticospinal neurons, and more particularly the signals that govern their birth and specification during development. She developed strategies to program and reprogram neuronal progenitors and post-mitotic neurons in vivo, and induced the specification of ectopic corticospinal neurons [Rouaux & Arlotta, Nat Neuro, 2010; Rouaux & Arlotta Nat Cell Biol, 2013]. In 2013, she returned to Strasbourg upon obtaining an Assistant Professor position at Inserm. In 2015, she was awarded an ERC Starting Grant to unravel the role of the motor cortex and its neuronal populations to ALS onset and progression and decipher the mechanisms that govern CSN selected degeneration [Burg et al., Ann Neurol, 2020; Scekic-Zahirovic et al., bioRxiv, 2020; Marques et al., bioRxiv, 2019]. With her team, her goal is now to design and test alternative therapeutic strategies for ALS, based on the maintenance of properly functioning cortical neurons and circuits.