Location, Location, Location

Abstract

Neurons may be particularly sensitive to disruptions in transcription factor trafficking. Survival and injury signals must traverse dendrites or axons, in addition to soma, to affect nuclear transcriptional responses. Transcription factors exhibit continued nucleocytoplasmic shuttling; the predominant localization is regulated by binding to anchoring proteins that mask nuclear localization/export signals and/or target the factor for degradation. Two functional groups of karyopherins, importins and exportins, mediate RanGTPase-dependent transport through the nuclear pore. A growing number of recent studies, in Alzheimer, Parkinson, and Lewy body diseases, amyotrophic lateral sclerosis, and human immunodeficiency virus encephalitis, implicate aberrant cytoplasmic localization of transcription factors and their regulatory kinases in degenerating neurons. Potential mechanisms include impaired nuclear import, enhanced export, suppression of degradation, and sequestration in protein aggregates or organelles and may reflect unmasking of alternative cytoplasmic functions, both physiologic and pathologic. Some "nuclear" factors also function in mitochondria, and importins are also involved in axonal protein trafficking. Detrimental consequences of a decreased nuclear to cytoplasmic balance include suppression of neuroprotective transcription mediated by cAMP- and electrophile/antioxidant-response elements and gain of toxic cytoplasmic effects. Studying the pathophysiologic mechanisms regulating transcription factor localization should facilitate strategies to bypass deficits and restore adaptive neuroprotective transcriptional responses.

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

“…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). 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).…”

Back to the tubule: microtubule dynamics in Parkinson’s disease

“…Interestingly, the oxidative neurotoxin 6-hydroxydopamine (6OHDA) was shown to influence SIRT2 activity and microtubule dynamics through more than one mechanism, leading to impaired nuclear import of certain transcription factors [93, 94]. Consistently, altered subcellular localisation of transcription factors has been reported in post-mortem PD brains [93, 95, 96]. …”

Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

“…The balance of cytoplasmic and nuclear location of E2F1 may play a role in pathological role of E2F1 in neurodegenerative disorders [55]. While RANTES alone has been shown to induce apoptosis through activation of caspase-9, caspase-3, release of cytochrome c and poly(ADP-ribose) polymerase cleavage, there is evidence that IFN-gamma stimulates RANTES which in turn produces apoptosis via stimulation of caspase-3 and caspase-9 [56, 57].…”