Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS–associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model. At high doses, SINE compounds block nuclear egress of an XPO1 cargo reporter, but not at lower concentrations that were associated with neuroprotection. Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, affecting approximately 2-3 per 100,000 individuals worldwide[1,2,3]
We conducted a careful study of selective XPO1 inhibition and nuclear TDP43 export in ALS and frontotemporal dementia (FTD) disease models
Within a defined therapeutic window, selective inhibitors of nuclear export (SINE) compounds modestly promote neuronal survival in primary neurons, and partially rescue a motor phenotype in rats overexpressing the RNA binding protein TDP43
Summary
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, affecting approximately 2-3 per 100,000 individuals worldwide[1,2,3]. In the majority of those with ALS and FTD, the pathologic hallmark of disease is the cytoplasmic deposition of the nuclear RNA binding protein TDP4317, implying a common mechanism underlying these clinically-overlapping neurodegenerative disorders. Strategies that effectively reduce cytoplasmic TDP43 concentrations, including the induction of macroautophagy (one of the major catabolic pathways active within the cytoplasm)[21], prevent neurodegeneration and extend cellular survival in models of ALS and FTD. These observations underscore the physiologic importance of cytoplasmic protein deposition in the pathogenesis of ALS and FTD. We conducted a careful study of SINE compounds and their therapeutic potential in both in vitro and in vivo disease models, testing the ability of these small molecules to prevent cytoplasmic TDP43 mislocalization and extend neuronal survival
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