RNA Processing in ALS

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).