Metabolism in frontotemporal dementia

Abstract

FrontoTemporal Lobar Degeneration (FTLD) is a highly heritable disorder with up to 50% of the cases reporting a positive family history. Mutations in 3 genes are responsible of most of these genetic cases: microtubule associated protein tau (MAPT), progranulin (PGRN) and chromosome 9 open reading frame 72 (C9orf72). Subsequently sporadic cases are mathematically responsible of more than 50% of the remaining cases. Genetic or sporadic FTLDs share common neuropathological features such as neuronal TDP43 or FUS inclusions. Thus, independently of the genetic origin and because of the global and significant neurodegeneration, mostly frontal and temporal, it seems highly probable that the different subtypes share some similar molecular mechanisms. In addition, to increase the level of complexity, either due to the different genetic origin or to the nature of the protein aggregates we can also expect some specific molecular mechanisms to be involved in the disease. We challenged these two non exclusive possibilities by analyzing the frontal cortex at the latest stage of the disease. High-throughput RNA sequencing was performed with a coverage sufficient to analyze not only transcriptome but also splicing profiles and antisense RNAs. The samples were sorted according to the genetic mutation they carry: C9orf72, MAPT and PGRN. In addition, we compared sporadic cases presenting TDP43 inclusions and a set of controls. Performing clustering analysis on the full set of data revealed that the mutations in MAPT and PGRN have an extremely homogenous RNA metabolism response while sporadic cases, controls, and C9orf72 mutant carriers have a surprisingly higher heterogeneity. Strikingly, this heterogeneity is increased even further when including already published RNAseq data from a set of controls (Prudencio et al. Nat Neurosci. 2015;18(8):1175-82). Nevertheless, we observed differences at transcriptional level that are mutation dependent. In addition, some splicing profiles are also specific of genetic mutations, while others appear to be linked to the type of pathology (FTLD, FTLD/ALS). With these results we clearly contribute to prove that FTLD are not only proteinopathies and spliceopathies but also general RNAopathies.