Altered transcription factor trafficking in oxidatively-stressed neuronal cells

Abstract

Age-related neurodegenerative diseases are associated with alterations in gene expression in affected neurons. One of the mechanisms that could account for this is altered subcellular localization of transcription factors, which has been observed in human post-mortem brains of each of the major neurodegenerative diseases, including Parkinson’s disease (PD). The specific mechanisms are yet to be elucidated; however a potential mechanism involves alterations in nuclear transport. In this study, we examined the nucleocytoplasmic trafficking of select transcription factors in response to a PD-relevant oxidative injury, 6-hydroxydopamine (6OHDA). Utilizing a well-established model of ligand-regulated nucleocytoplasmic shuttling, the glucocorticoid receptor, we found that 6OHDA selectively impaired nuclear import through an oxidative mechanism without affecting nuclear export or nuclear retention. Interestingly, impaired nuclear import was selective as Nrf2 (nuclear factor E2-related factor 2) nuclear localization remained intact in 6OHDA-treated cells. Thus, oxidative stress specifically impacts the subcellular localization of some but not all transcription factors, which is consistent with observations in post-mortem PD brains. Our data further implicate a role for altered microtubule dependent trafficking in the differential effects of 6OHDA on transcription factor import. Oxidative disruption of microtubule-dependent nuclear transport may contribute to selective declines in transcriptional responses of aging or diseased dopaminergic cells.

The importin α subunit PsIMPA1 mediates the oxidative stress response and is required for the pathogenicity of Phytophthora sojae

“…Oxidative stress was shown to induce nuclear translocation of the transcription factors MoAP1, AaAP1, and UmYAP1 (Guo et al, 2011;Lin et al, 2009;Molina and Kahmann, 2007). Oxidative damage to proteins, lipids, and DNA is found in the brains of autopsy patients with various neurodegenerative diseases, including Parkinson's disease, and the involvement of transcription factors in this type of cellular stress has been suggested (Patel et al, 2012). The human transcription factors NF-jB and Nrf2 are translocated into the nucleus as part of antioxidant defense processes (Kodiha and Stochaj, 2012).…”

Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: Implications for Parkinson's disease

“…After being taken up into cells by dopamine reuptake transporters, it generates reactive oxygen species (ROS) through several mechanisms that include redox-cycling autoxidation, oxidation by monoamine oxidases, and the secondary onset of mitochondrial dysfunction (Blum, et al, 2001; Kulich et al, 2007; Przedborski and Ischiropoulos, 2005). 6OHDA alters the subcellular localization of certain transcription factors (Dagda et al, 2008; V. P. Patel et al, 2012; Zhu et al, 2002), leading to alterations in gene transcription and decreased survival of midbrain neurons and catecholaminergic SH-SY5Y cells (Chalovich et al, 2006). These findings are consistent with changes observed in degenerating midbrain neurons of post-mortem PD brains (C. T. Chu et al, 2007).…”

“…These findings are consistent with changes observed in degenerating midbrain neurons of post-mortem PD brains (C. T. Chu et al, 2007). Moreover, 6OHDA affects the levels of polymerized tubulin, and selectively impairs the nuclear import of a MT-sensitive transcription factor (V. P. Patel, et al, 2012). In this study, we utilized both a pre-lethal and a sub-lethal 6OHDA injury paradigm to examine in detail the impact of oxidative stress on MT dynamics.…”

The Nervous System Cytoskeleton under Oxidative Stress

“…It seems likely that the breakdown in transport of cargoes along microtubules due to defects in tubulin acetylation may play a key role in promoting oxidative stress and subsequent neurodegeneration, whereas increased α-tubulin acetylation and microtubule-based transport may act to alleviate oxidative stress. Transcription factor trafficking is also affected in oxidatively-stressed neurons [23].…”