Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a devastating disease with a lifetime risk of approximately 1:400. It is incurable and invariably fatal. Average survival is between 3 and 5 years and patients become increasingly paralyzed, losing the ability to speak, eat, and breathe. Therapies in development either (i) target specific familial forms of ALS (comprising a minority of around 10% of cases) or ii) emanate from (over)reliance on animal models or non-human/non-neuronal cell models. There is a desperate and unmet clinical need for effective treatments. Deciphering the primacy and relative contributions of defective protein homeostasis and RNA metabolism in ALS across different model systems will facilitate the identification of putative therapeutic targets. Areas covered: This review examines the putative common primary molecular events that lead to ALS pathogenesis. We focus on deregulated RNA metabolism, protein mislocalization/pathological aggregation and the role of glia in ALS-related motor neuron degeneration. Finally, we describe promising targets for therapeutic evaluation. Expert opinion: Moving forward, an effective strategy could be achieved by a poly-therapeutic approach which targets both deregulated RNA metabolism and protein dyshomeostasis in the relevant cell types, at the appropriate phase of disease.

Stress-Specific Spatiotemporal Responses of RNA-Binding Proteins in Human Stem Cell-Derived Motor Neurons

“…The ALS-causing VCP mutations R155C and R191Q in this study did not show nucleocytoplasmic transport defects following cellular stress, despite a reduction in their nuclear-to-cytoplasmic ratios under basal conditions. ALS results from a wide variety of genetic insults, and multiple mechanisms are involved in the disease pathogenesis, accounting for the differences in nucleocytoplasmic defects [49]. Taken together, our findings suggest that the basal TDP-43 and FUS mislocalisation observed in VCP mutant MNs is not (at least initially) caused by failure of their nuclear relocalisation following cellular stress.…”

Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno‐associated viral vectors

“…Through this binding, ASOs are able to modify RNA processing and protein expression through distinct mechanisms. The benefit of this method for targeting SFPQ is that the ASO may be designed specifically to bind to the retained‐intron proportion of SFPQ , thereby preventing RBPs such as FUS and SFPQ from binding to the aberrantly retained intronic portion explored above while retaining the function of correctly spliced SFPQ 118 . Although it is unlikely that this is the only mechanism of FUS mislocalisation in ALS pathogenesis, it is potentially an important contributing factor 110 .…”

“…The benefit of this method for targeting SFPQ is that the ASO may be designed specifically to bind to the retained-intron proportion of SFPQ, thereby preventing RBPs such as FUS and SFPQ from binding to the aberrantly retained intronic portion explored above while retaining the function of correctly spliced SFPQ. 118 Although it is unlikely that this is the only mechanism of FUS mislocalisation in ALS pathogenesis, it is potentially an important contributing factor. 110 Building on the above study, Tyzack et al 119 identified an additional pool of >100 intron-retained transcripts within human ALS-mutant iPSCs that demonstrated increased cytoplasmic localization.…”