From the investigation of the role of SRSF1 in ALS/FTD to its targeting as a therapeutic strategy
Prof. Frédéric Allain, ETH Zürich
Abstract (lay summary see below)
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases. ALS is characterized by progressive muscular weakness and wasting caused by the degeneration of motor neurons controlling voluntary muscles. Patients with FTD experience progressive aphasia and personality changes. However, both conditions can manifest themselves in motor neuron dysfunction, behavioural and cognitive changes indicating that ALS and FTD might be related diseases. GGGGCC hexanucleotide-repeat expansion (HRE) located in intron 1 of C9orf72 was established as the most frequent genetic cause of familial ALS and FTD. A typical healthy person carries no more than thirty repeats of G4C2 hexanucleotides, while patients suffering from FTD or ALS may bear expansion ranging from hundreds to thousands of repeats. C9orf72 HRE is transcribed in both sense and antisense directions leading to the formation of nuclear RNA foci. The RNA foci are membrane-less organelles enriched in HRE transcripts, cellular RNAs, and proteins with prion-like and intrinsically disordered domains. Recent investigations showed that the interaction of the human SR protein SRSF1 with the HRE is responsible for their export in the cytoplasm and their subsequent translation into toxic peptides, which lead to c9ALS/FTD symptoms. In addition, SRSF1 was also found in the HRE-containing nuclear foci.
We propose here to unravel this network of connected events by characterizing the mode of interaction of SRSF1 with the HRE using NMR and understanding what leads to the formation of the nuclear foci containing SRSF1 and HRE. We will also investigate whether these nuclear foci could act as a protective cellular process by storing the HRE and preventing their export to the cytoplasm. In addition, we will try to identify the conditions that lead to the release of these HRE from the nuclear foci as it could be a cause of their leak to the cytoplasm. Finally, we will also try to find new therapeutic strategies against ALS/FTD by preventing SRSF1 interaction with these HRE. The goal is to prevent this interaction to prevent HRE export to the cytoplasm. We aim here at screening our in-house large library of small molecules to identify some that prevent SRSF1 binding to HRE using NMR. In addition, we will also investigate whether this interaction could be avoided by the use of ASOs complementary to the HRE or acting as sponges to saturate SRSF1 binding sites.
Lay summary
La sclérose latérale amyotrophique (SLA) et la démence fronto-temporale (DFP) sont des maladies neurodégénératives. La SLA se caractérise par une faiblesse musculaire progressive et une atrophie causée par la dégénérescence des motoneurones contrôlant les muscles volontaires. Les patients atteints de DFP présentent une aphasie progressive et des changements de personnalité. Cependant, les deux conditions peuvent se manifester par un dysfonctionnement des motoneurones, des changements comportementaux et cognitifs indiquant que la SLA et la DFP pourraient être des maladies liées. L'expansion répétée de l'hexanucléotide GGGGCC (HRE) située dans l'intron 1 de C9orf72 a été établie comme la cause génétique la plus fréquente de la SLA familiale et de la DFP. Une personne en bonne santé ne porte pas plus de trente répétitions d'hexanucléotides G4C2, tandis que les patients souffrant de DFP ou de SLA peuvent avoir une expansion allant de centaines à des milliers de répétitions. C9orf72 HRE est transcrit dans les directions sens et anti-sens conduisant à une accumulation de ces ARN dans le noyau. Ils forment des organites sans membrane enrichis en transcrits HRE, en ARN cellulaires et en protéines avec des domaines de type prion et intrinsèquement désordonnés. Des recherches récentes ont montré que l'interaction de la protéine SR humaine SRSF1 avec le HRE est responsable de leur exportation dans le cytoplasme et de leur traduction ultérieure en peptides toxiques, qui conduisent à des symptômes c9ALS/FTD. De plus, SRSF1 a également été trouvé dans ces agrégats nucléaires contenant les HRE.
Nous proposons ici de démêler ce réseau d'événements connectés en caractérisant le mode d'interaction de SRSF1 avec le HRE en utilisant la RMN et de comprendre ce qui conduit à la formation des agrégats nucléaires contenant SRSF1 et HRE. Nous étudierons également si ces organites pourraient agir comme un processus cellulaire protecteur en stockant les HRE et en empêchant leur exportation vers le cytoplasme. De plus, nous essaierons d'identifier les conditions qui conduisent à la libération de ces HRE des agrégats nucléaires car cela pourrait être une cause de leur fuite vers le cytoplasme. Enfin, nous essaierons également de trouver de nouvelles stratégies thérapeutiques contre la SLA/DFP en empêchant l'interaction de SRSF1 avec ces HRE. L'objectif est d'empêcher cette interaction pour limiter l'exportation de HRE vers le cytoplasme. Nous proposons ici de cribler notre grande bibliothèque interne de petites molécules pour en identifier certaines qui empêchent la liaison de SRSF1 à HRE en utilisant la RMN. De plus, nous étudierons également si cette interaction pourrait être évitée par l'utilisation d'oligonucléotides anti-sens complémentaires au HRE ou agissant comme des éponges pour saturer les sites de liaison de SRSF1.
Progetti
- Nuovi progetti di ricerca dal 2024
- L'importanza della ricerca
- Progetti finanziati
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- Molecular signature, metabolic profile and therapeutic potential of human myogenic reserve cells
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- Targeting NADPH oxidase 4 in models of Duchenne muscular dystrophy
- Characterizing the role of ER stress in C9orf72-linked ALS pathology
- Inducing mitophagy with Urolithin A to restore mitochondrial and muscle function in muscular dystrophy
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- Role and therapeutic potential of PLIN3 in neuromuscular diseases
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- Protective effects and mechanisms of action of tamoxifen in mice with severe muscular diseases
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- Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
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- Deciphering the pathogenic mechanisms of C9ORF72 ALS
- Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs
- Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
- Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
- Improving cellular therapies of muscle dystrophies by uncovering epigenetic and signaling pathways of muscle formation
- Protein engineering in an attempt to increase the mechanical, integrin dependent cytoskeleton-matrix linkage in muscle fibers
- Muscle velocity recovery cycles: a new tool for characterization of muscle disease in vivo
- Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy?
- Evaluation of novel treatment strategies for dyspherlinopathies in mouse models
- Cell therapy of LGMD2D by donor HLA-characterized human mesoangioblasts (hMABs) produced in GMP conditions
- In search of small molecules targeting protein-RNA complex: a novel approach against Spinal Muscular Atrophy
- Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies
- Development of magnetic resonance methods for functional imaging of the skeletal muscle
- Targeting ER stress response: a potential mechanism for neuroprotection in Amyotrophic Lateral Sclerosis
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
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