THEME III: Structure: function of mRNA-binding proteins involved in neurodegeneration

RNA Binding Proteins harboring a Low Complexcity Domain: angel or evil?

Neurodegenerative diseases are intimately linked to ageing and understanding the mechanisms underlying neurodegenerative disorders and providing them with a therapeutic solution has become a public health issue in developed countries where life expectancy is high. Unfortunately, age-related neurodegenerative disorders such as Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Parkinson’s Disease (PD), and Huntington’s Disease (HD) have still not found an effective therapeutic response and treatments do not yet target the origin of the disease but try to mitigate its effects. All these diseases have in common the accumulation of poorly structured proteins in the brain. Tau protein and the Aβ peptide in the cortex and the hyppocampus of patients suffering from AD or the α-synuclein which aggregates in the cytoplasm of the neurons of people affected by PD are the first ones to come in mind. In the last decade, the development of high-throughput approaches has isolated other major protein constituents of aggregates that accumulate in the brain of patients affected by neurodegenerative diseases like ALS, FTD or HD. Among these proteins, RNA-binding proteins (RBPs), which are involved in various steps of RNA metabolism,are over represented. The identified RBPs have in common the presence of one or more RNA-binding domains called RNA recognition motifs (RRM) and a Low Complexity Domain (LCD) that is prone to aggregation. Following their identification, the transition of these proteins from a functional soluble state in healthy patients to an aggregated state in patients suffering from these neurodegenerative syndromes becomes a major issue. Of course, there are some genetic explanations and mutations in the genes encoding the proteins of interest have been identified in many familial cases of diseases attesting the active role of RBPs in dementia. However, a link between cellular stress and RBP aggregation was also proposed via the formation of Stress Granules (SGs) which are cytoplasmic micrometric structures constituted by RBP and non polysomal RNA and repetition of SG assembly/disassembly could be considered as a mechanism that favors aggregation of RBPs containing LCD.

Three RBPs with LCD(FUS, TDP-43) or without LCD (RBM-45) are specifically studied in the theme III due to their implication in neurodegeneration. In the neurons of healthy patients, these proteins are mainly localized in the nucleus but they form fibrillar aggregates in the cytoplasm when patients are affected by ALS or FTD. Both are implied in SG assembly via the RRM and LCD domains and are responsible for the liquid-like properties of SGs. Using in vitro approaches, we are focusing our research on:

Influence of RNA on RBPs with LCD aggregation (RNA sequence, protein mutations, mechanism of multimerization, cooperativity)

Structural features of protein aggregates (AFM image of FUS fibrils 400 x 400 nm)

Influence of other RBPs (like YB-1 or G3BP) on TDP-43 and FUS aggregation

Theme III gathered skills in biochemistry of protein/RNA interactions, protein and RNA productions, NMR analysis and Atomic Force Microscopy Imaging.

Principal Investigator: Ahmed Bouhss (CR, CNRS) and Loic Hamon (MCU, UEVE)

Members:

Marie-Jeanne Clément-Lai Cheong (IR, UEVE)

Guillaume Lambert (IE, INSERM)

Vandana Joshi, (IE, INSERM)

Juan Rengifo Gonzalez (PhD student, ED SDSV)

Anastasiya Singatulina (PhD student, Vernadsky Program)

Serhii Pankivskyi (PhD student, Eiffel Program)

Clément Demongin (PhD student, ED SDSV)