The tail domain of neurofilament light chain accumulates in neuronal nuclei during oxidative injury

Abstract

AbstractNeurofilament light chain (NFL), one of the major subunits of neuron-specific intermediate filaments, is an important component of the neuronal cytoskeleton. Mutations in the NEFL gene and disturbances of NFL turnover or transport are associated with the pathophysiology of various diseases of the nervous system. Also, NFL is released from neurons as a result of neuroaxonal damage and NFL levels in cerebrospinal fluid and blood have emerged as a biomarker of the progression of numerous neurological diseases. One common underlying factor in these diseases is oxidative stress. Although both NFL and oxidative injury play a role in the development of neurological diseases, the effect of oxidative stress on NFL at the cellular level has not been extensively studied. Here, by investigating the response of neurofilaments to in vitro oxidative injury, we discovered that NFL localizes in the nuclei of primary neurons. We show that this depends on calpain activity and determine that a proteolytic fragment of the tail domain, not the full-length NFL, is that which accumulates in the nuclei. Furthermore, we demonstrate that the recombinant NFL tail domain accumulates in the nuclei of neurons and neuroblastoma cells, even in the absence of oxidative injury. Finally, we show that the tail domain of NFL interacts with the DNA in the nuclei of living cells, suggesting that NFL plays a role in the regulation of gene expression in response to oxidative injury.