First Thesis Advisor
Daryl A. Bosco
excitotoxicity, FUS, amyotrophic lateral sclerosis, nucleocytoplasmic transport, Gria2, neurodegeneration
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by motor neuron loss. Although pathological mutations exist in >15 genes, the mechanism(s) underlying ALS are unknown. FUS is one such gene and encodes the nuclear RNA-binding protein (RBP), fused in sarcoma (FUS), which actively shuttles between the nucleus and cytoplasm. Intriguingly, nearly half of the ALS mutations identified in FUS cause this protein to mislocalize, suggesting that FUS localization is relevant to disease.
Here, we found that excitotoxicity, a neuronal stress caused by aberrant glutamate signaling, induces the rapid redistribution of FUS and additional disease-linked RBPs from the nucleus to the cytoplasm. As excitotoxicity is pathologically associated with ALS, it was notable that the nuclear egress of FUS was particularly robust. Further, ALS-FUS variants that predominantly localize to the nucleus also undergo redistribution. Thus, we sought to understand the purpose underlying FUS translocation and the potential relevance of this response to disease. As calcium dysregulation is strongly associated with neurodegenerative disorders, we examined the contribution of calcium to FUS egress. In addition to global changes to nucleocytoplasmic transport following excitotoxic insult, we observed that FUS translocation caused by excitotoxicity is calcium mediated. Moreover, we found that dendritic expression of Gria2, a transcript encoding an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit responsible for regulating calcium permeability, is FUS-dependent under conditions of stress. Together, these observations support the premise that FUS has a normal function during excitotoxic stress and that glutamatergic signaling may be dysregulated in FUS-mediated ALS.
Tischbein, M. FUS and Excitotoxicity Cross Paths in ALS: New Insights into Cellular Stress and Disease. (2018). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 990. DOI: 10.13028/e3yk-qp82. https://escholarship.umassmed.edu/gsbs_diss/990
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