Examining cross-species suppression of neurodegeneration by loss of a conserved RNA binding protein in models of ALS and FTD

点击翻译按钮获取中文摘要

Etiological mechanisms for Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are poorly defined, but mutations in multiple genes can cause FTD, ALS, or a mixed clinical syndrome. This suggests that common molecular pathways underlie disease pathogenesis. Phenotype-based genetic studies in model organisms are a powerful strategy for identifying these pathogenic mechanisms and potential therapeutic targets. Here, we focus on a conserved RNA-binding protein, which suppresses pathology in a genetic model for ALS in C. elegans. We propose to initiate analysis of the mechanism of suppression and to test for beneficial effects in additional FTD/ALS models in both C. elegans and mice. Historically, work in the FTD/ALS field has relied on animal models that mis- or over-express disease proteins. However, disease proteins are not over-expressed in patients, over-expression of wild-type protein is often toxic, and disentangling disease mechanisms from artificial effects of mis-/over-expression is therefore challenging. Instead, we primarily rely on knock-in models, created by directly editing the endogenous genes to insert patient amino acid changes. In our C. elegans knock-in model for sod-1G85R, we observe stress-induced degeneration of cholinergic and glutamatergic neurons, but not loss of dopaminergic or serotonergic neurons. A similar approach was used to develop the mouse knock-in mouse model for Sod1G85R, which exhibits progressive motor neuron degeneration. We undertook the first genetic suppressor screen using a knock-in animal model and identified an RNA-binding protein whose loss of function suppresses both glutamatergic and cholinergic neurodegeneration in knock-in sod-1G85R C. elegans. Intriguingly, a vertebrate ortholog of this RNA-binding protein is found in RNA/protein granules in axonal processes, along with HNRNPA1, FUS, and other proteins whose mutation causes FTD/ALS, and was identified as a suppressor of C9orf72-associated dipeptide repeat-induced toxicity. Understanding how loss of this RNA binding protein suppresses neurodegeneration may provide insights into why mutation of SOD1, HNRNPA1, FUS, or other proteins leads to FTD/ALS. In our first aim, we plan to identify the mechanism of suppression in C. elegans and examine the ability of this suppressor to decrease degeneration in other models of FTD/ALS (C9orf72, HNRNPA1, FUS, and TDP43). Further, it is important to determine whether loss of this RNA binding protein can also suppress degeneration in vertebrate models. In the second aim, we assess conservation of suppression in the murine SOD1G85R knock-in model. Combined, these aims will provide insight into pathogenic mechanisms, may link SOD1-associated ALS to FTD/ALS caused by mutation of other RNA-binding proteins (e.g. FUS), and will help determine if future in-depth studies in vertebrate models are warranted to develop therapeutic interventions that target the RNA-binding protein encoded by this suppressor gene.