Loss of FXR1 and FXR2 promotes accumulation of TDP-43 in aging-related stress granules

Abstract

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 in vulnerable neurons may accompany the primary neuropathology of various neurodegenerative diseases, or represent the hallmark of others, such as amyotrophic lateral sclerosis. Aging is the major risk factor for neurodegeneration, and sufficient to induce accumulation of TDP-43 in chronic cytoplasmic stress granules possibly further maturing to irreversible aggregates. Reduced expression of Fragile X protein (FXP) family members (FMR1, FXR1 and FXR2) in vulnerable neurons is associated with neurodegeneration, and loss of each individual FXP induces overlapping and unique aging-related phenotypes in HAP1 and SH-SY5Y cell models. Therefore, we analyzed consequences of FXP loss on TDP-43 cytoplasmic mislocalization and stress granule formation in fibroblast-like HAP1 FXP knockout cells. FXP loss induced nuclear pore pathology, and passive egress of proteins and RNA was evident upon loss of FXR1 or FXR2. Cytoplasmic mislocalization of TDP-43 was restricted to FXR1 knockout cells upon impairment of nuclear import, and cytoplasmic TDP-43 induced spontaneous stress granules exclusively in FXR2 knockout cells. In contrast, loss of FMR1 had no effect on nucleocytoplasmic exchange or TDP-43. Hence, reduced expression of FXR1 and FXR2 in aging and neurodegeneration may contribute to TDP-43 pathology.