Biology subjects

Rouaux, C.

Publications and source records attributed to Rouaux, C..

4 recordsLinked to original sources

bioRxiv2024

CREB3 gain of function variants protect against ALS

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease that arises from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). The disease is mostly sporadic, but genetics is expected to highly contribute to disease onset and progression. Genome wide association studies identified a few genetic disease modifiers, mostly associated with a negative outcome, and demonstrated that ALS is primarily a disease of excitatory glutamatergic neurons. Here, we reasoned that at least a subpart of genetic disease modifiers may directly modulate the molecular pathways selectively activated in vulnerable neurons as the disease progresses, and concentrated on CSN for their selective vulnerability and glutamatergic identity. We implemented comparative cross-species transcriptomics using snRNAseq data from postmortem motor cortex of ALS patients and controls, and longitudinal RNAseq data from anatomically defined CSN purified from the Sod1G86R mouse model of ALS. We report that disease vulnerable neuronal populations undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of neuronal dysfunction in ALS. Using genetic and epidemiologic analyses we further identify the rare variant CREB3R119G (rs11538707) as a new disease modifier in ALS. Through gain of function, CREB3R119G decreases both the risk of developing ALS and the progression rate of ALS patients. This study reveals novel genetic variants that protect against ALS and highlights the benefice of combining transcriptomics and genetics to identify new disease modifiers and therapeutic targets.

genomics↗

bioRxiv2020

Genetic ablation of SOD1G37R selectively from corticofugal projection neurons protects corticospinal neurons from degeneration without affecting ALS onset and progression

While clinical evidence of combined degeneration of the bulbar and spinal motor neurons (MN) together with the corticospinal neurons (CSN) is required to diagnose Amyotrophic Lateral Sclerosis (ALS), preclinical studies have mostly concentrated on MN, leaving aside the CSN and their contribution to ALS onset and progression. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets, along the corticofugal axonal projections (including CSN), either via altered neuronal excitability and subsequent excitotoxicity, or via prion-like propagation of misfolded proteins. We recently provided first experimental arguments in favour of the corticofugal hypothesis of ALS, demonstrating that CSN and other subcerebral projection neurons were toxic in a context of ALS. Here, we aimed to determine how CSN may be detrimental to their downstream targets, and what governs their degeneration. To answer these questions, we took advantage of the FloxedSOD1G37R mouse model of ALS that allows genetic ablation of the mutant transgene in selected cells upon Cre-mediated recombination, and crossed it to the CrymCreERT2 mouse line that we purposely designed to genetically target CSN and other corticofugal projection neurons (CFuPN) populations. We demonstrate that excision of the mutant SOD1G37R transgene from the CSN is sufficient to prevent their death, suggesting that CSN degeneration mostly relies on cell-intrinsic mechanisms. However, genetic ablation of SOD1G37R transgene from the corticofugal neurons had no effect on disease onset and survival. The data thus indicate that the toxicity of CFuPN in the context of ALS, and corticofugal propagation of the disease, are not mediated by the presence of misfolded mutant proteins, but more likely by other aspects of the cortical pathology, possibly hyperexcitability.

neuroscience↗

bioRxiv2019

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this "corticofugal hypothesis" of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in Sod1G86R mice, a mouse model of ALS. Ablation of the transcription factor Fezf2, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.

neuroscience↗

bioRxiv2019

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.

neuroscience↗