Several RNA binding proteins have been found in proteinaceous aggregates, a hallmark of neurodegeneration, which suggests that they are involved in the pathomechanism of disease. Additionally, some have been shown to harbor mutations causing amyotrophic lateral sclerosis (ALS) and/or related neurodegenerative diseases such as frontotemporal degeneration (FTD). Among these, TDP-43 is linked to the vast majority of ALS cases (>95%) and has been implicated in RNA splicing, transport, storage in RNA stress granules (SGs), and translation. These data suggest intimate links between TDP-43, RNA metabolism, and disease. Our overarching hypothesis is that TDP-43 acts as a regulator of mRNA localization and translation in motor neurons, and that dysregulation of these processes contributes to the pathophysiology of ALS. This hypothesis is tested using a combination of molecular, genetic, imaging, bioinformatics, and functional approaches. We expect this research to provide novel insights into TDP-43’s function in translation, to identify physiologically significant and disease-relevant protein partners and mRNA targets, which in turn may pinpoint much-needed molecular targets and pathways with therapeutic potential for ALS and related neurodegenerative diseases.
RNA binding protein partners of TDP-43Using a Drosophila model of ALS we developed we recently demonstrated that Fragile X Protein (FMRP), an established translational regulator that our group has previously worked on, is neuroprotective by reducing TDP-43 aggregation and restoring the translation of specific mRNA targets (Figure 1).
Figure 1. A model for TDP-43 – FMRP interaction. Similar to what has been observed in the human disease, TDP-43 overexpression (OE) results in the formation of RNA SGs that persist. These RNA SGs cause sequestration of mRNA targets and translation inhibition. FMRP OE is neuroprotective and modulates TDP-43 solubility. FMRP OE restores TDP-43 dependent translation inhibition of specific mRNA targets.
Our current efforts are aimed at understanding the physical interactions between TDP-43, FMRP and other RNA binding proteins in temporary mRNA-storage stress granules (SGs), including granule components and translation initiation factors that we have identified using biochemical and/or genetic approaches. These experiments are expected to provide a mechanistic view of TDP-43’s role in translation and identify strategies for remodeling RNA granules with small molecules (see Drug Discovery in Drosophila paragraph below).