Analyses of thousands of molecular events, example of RNA metabolism in Fronto-Temporal Dementias

Vincent Anquetil (ICM)
Thursday, February 28, 2019 - 10:30 to 12:00
Room Aurigny
Talk abstract: 

FrontoTemporal dementias (FTD) are characterized by progressive behavioral and language changes, associated with an atrophy of the frontal and temporal lobes. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal motor neuron disease. If ALS is a poorly heritable disorder (about 10%), up to 50% of the FTD correspond to forms with genetic transmission. Mutations in 3 genes are responsible for most of the FTD genetic cases: microtubule associated protein tau (MAPT), progranulin (PGRN) and chromosome 9 open reading frame 72 (C9orf72). Genetic or sporadic FTDs share common neuropathological features such as neuronal Tubulin-Associated Unit (TAU), Tar-DNA binding Protein 43 (TDP43), or Fused in Sarcoma (FUS) inclusions. TDP43 and FUS neuronal inclusions are common to FTD and ALS. Up to 50% of ALS patients develop FTD symptoms and around 15% of FTD patients display motor neuron dysfunction typical of ALS. To date, no treatment is available for these disorders, and the molecular mechanisms at stake in the different pathological subtypes remain elusive.We analyzed, at the molecular level, the affected (frontal) and preserved (occipital) cortices of FTD +/- ALS patients. High-throughput RNA sequencing was performed to analyze transcriptome, splicing profiles and micro-RNAs misregulation for a subset. The samples were sorted according to their genetic mutation (C9orf72, MAPT, PGRN), neuropathology (TAU+, TDP+, FUS+), phenotype (FTD, FTD+ALS, ALS) and compared to a set of controls. Gene expression data allowed to differentiate the three phenotypes: pure FTD, pure ALS and FTD/ALS. Hundreds of differential RNA maturation profiles (splicing) were observed between mutations. Globally, less than 10% of the computed changes in RNA processing lead to modification of RNA expression. Therefore, the differently processed mRNAs can lead to the synthesis of 1) a different ratio of existing proteins 2) mis-localization of the newly synthesized protein 3) the synthesis of aberrant proteins in FTD patients. So, these diseases known as proteinopathies can be due to an accumulation of RNA processing defects, making FTD +/- ALS also general RNAopathies.