Role of oligodendroglial dysfunction in ALS and FTLD pathogenesis

01.05.2021 bis 30.04.2024

Cytoplasmic aggregation of the nuclear DNA/RNA-binding protein TDP-43 with inclusion body formation is the hallmark pathological feature in two devastating neurodegenerative diseases subsumed as primary TDP-43 proteinopathies: frontotemporal lobar degeneration with TDP-43 pathology (FTLD–TDP), and the vast majority of amyotrophic lateral sclerosis (ALS–TDP). ALS/FTLD-TDP can be sporadic or familial with genetic forms including mutations in the genes TARDBP, GRN and C9orf72. Given the intimate association between cytoplasmic accumulation of modified TDP-43 species with depletion of TDP-43 from the nucleus, current consensus is that most likely a combination of complex disturbances due to loss of nuclear and cytoplasmic TDP-43 functions and gain of toxic functions through aggregates is involved in the disease pathogenesis. Most previous and current research to dissect the pathomechanism is focused on neurons. However, we and others demonstrated that in addition to neurons, oligodendrocytes are strongly affected by TDP-43 pathology. Oligodendrocytes play crucial roles in neuronal functions and survival as well as in regulating neuronal circuitries by ensheating axons in the CNS with myelin and by providing metabolic support to axons. Thus, the overall goal of our project is to determine the impact and contributions of oligodendroglial alterations in the disease pathogenesis and disease process of ALS-TDP and FTLD-TDP. The analysis of unique and novel TDP-43 knock-in mouse lines and of a large collection of human postmortem CNS tissues from ALS/FTLD-TDP cases for genome wide and cell type specific transcriptome alterations using next-generation sequencing approaches will allow to dissect the physiological roles of TDP-43 in maturation and proper functioning of oligodendroglial lineage cells, and to determine molecular changes in oligodendroglia due to TARDBP mutations and in the disease process. Identifying specific transcriptomic signatures and altered pathways in oligodendrocytes would not only add to our fundamental understanding of the pathomechanisms underlying TDP-43 proteinopathies, but may pave the way for new therapeutic approaches in ALS/FTLD-TDP aiming to modulate oligodendrocyte metabolism and functions.