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Location, location, location: Altered transcription factor trafficking in neurodegeneration
被引:57
作者:
Chu, Charleen T.
Plowey, Edward D.
Wang, Ying
Patel, Vivek
Jordan-Sciutto, Kelly L.
机构:
[1] Univ Pittsburgh, Sch Med, Div Neuropathol, Dept Pathol, Pittsburgh, PA USA
[2] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA USA
[3] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA
[4] Univ Pittsburgh, Ctr Environm Basis Human Dis, Pittsburgh, PA USA
[5] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA
关键词:
Alzheimer disease;
cyclic AMP response element-binding protein;
karyopherins;
neurodegeneration;
oxidative stress;
Parkinson disease;
transcription factors;
D O I:
10.1097/nen.0b013e318156a3d7
中图分类号:
R74 [神经病学与精神病学];
学科分类号:
摘要:
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.
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页码:873 / 883
页数:11
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