Shared Functional Connections Between TDP-43 and RGNEF Proteins in Disease.

Abbassi, Yasmine (2024). Shared Functional Connections Between TDP-43 and RGNEF Proteins in Disease. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00101170

Abstract

Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA binding protein. RGNEF is known to act as a destabilising factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localise with inclusions of TDP-43, the major well-known RNA binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterise their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TARDBP and ARHGEF28 and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA binding factors that can be co-aggregating in neuronal cells.