D'Angelo MA, Raices M, Panowski SH, Hetzer MW.
Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells.
Cell. 2009 Jan 23;136(2):284-95.
PubMed.
The implications of this study for aging of the brain as well as for neurodegenerative disorders are potentially profound. The postulated link between brain aging and the aging of nuclear pore proteins is intriguing. For Alzheimer disease, concepts of pathogenesis are increasingly focusing on targets alternative to, or upstream of, β amyloid deposition. Critical events in the cell nucleus have garnered well-deserved attention in this regard. Histone deacetylases, transcriptional regulation, and DNA repair have taken center stage. The study by Hetzer's group brings the nuclear pores, the gateway to the nucleus, into the mix. Particularly provocative is the implication that aged and/or oxidatively damaged leaky pores allow the ectopic nuclear localization of cytoplasmic proteins, in this case, class III β tubulin. Could this represent a detrimental consequence of age-associated nuclear pore dysfunction? Do the intranuclear tubulin aggregates that form in "leaky" nuclei negatively influence nuclear function? The analogy would be with intranuclear inclusions that characterize other neurodegenerative diseases like Huntington disease. These have been shown to sequester important nuclear proteins like transcription factors, resulting in transcriptional dysregulation. We have published evidence for alterations in β tubulin-immunoreactive structures (intranuclear rodlets; INRs) in neurons in Alzheimer disease. The question now, in light of Hetzer's paper, is whether INRs are a morphological "readout" for leaky nuclei? If so, could the formation of these structures as a consequence of nuclear leakiness lead to transcriptional dysregulation and other intranuclear alterations lying upstream of β amyloid dysmetabolism? In this context, the paper by Hetzer's group could provide the foundation for a novel pathogenetic framework for AD. Finally, the implications of this study extend beyond the brain tor postmitotic cells in other organs such as the endocrine pancreas and for diseases associated with these cells including diabetes.
Recent attention has been drawn to potential dysfunction of nuclear-cytoplasmic transport and the nuclear pore complex (NPC) in neurodegenerative disorders. In their intriguing report, Hetzer and colleagues used functional assays to demonstrate age-dependent deterioration of NPC. They found malfunction of a structural component of the NPC (Nup93) associated with increased nuclear permeability that was accelerated by reactive oxygen species. Their finding of nuclear accumulation of the cytoplasmic protein, tubulin, in aged rat neurons suggested that loss of nuclear integrity allows nuclear aggregation of cytoplasmic proteins.
In fact, abnormal transport may be bidirectional; nuclear transcription factors have been demonstrated in neuronal cytoplasm in Alzheimer disease and other common neurodegenerative disorders where they may influence abnormal protein aggregation. Together, the convergence of factors implicated in Hetzer's report, i.e., aging, nuclear integrity, abnormal protein aggregation, and oxidative stress, suggests a potential mechanism for neurodegeneration in human disease. Indeed, similar study of neurons in aged human brain and Alzheimer disease is warranted. If confirmed, the question as to whether this finding represents a key initiating event or is epiphenomenal would remain.
Comments
Ottawa Hospital
The implications of this study for aging of the brain as well as for neurodegenerative disorders are potentially profound. The postulated link between brain aging and the aging of nuclear pore proteins is intriguing. For Alzheimer disease, concepts of pathogenesis are increasingly focusing on targets alternative to, or upstream of, β amyloid deposition. Critical events in the cell nucleus have garnered well-deserved attention in this regard. Histone deacetylases, transcriptional regulation, and DNA repair have taken center stage. The study by Hetzer's group brings the nuclear pores, the gateway to the nucleus, into the mix. Particularly provocative is the implication that aged and/or oxidatively damaged leaky pores allow the ectopic nuclear localization of cytoplasmic proteins, in this case, class III β tubulin. Could this represent a detrimental consequence of age-associated nuclear pore dysfunction? Do the intranuclear tubulin aggregates that form in "leaky" nuclei negatively influence nuclear function? The analogy would be with intranuclear inclusions that characterize other neurodegenerative diseases like Huntington disease. These have been shown to sequester important nuclear proteins like transcription factors, resulting in transcriptional dysregulation. We have published evidence for alterations in β tubulin-immunoreactive structures (intranuclear rodlets; INRs) in neurons in Alzheimer disease. The question now, in light of Hetzer's paper, is whether INRs are a morphological "readout" for leaky nuclei? If so, could the formation of these structures as a consequence of nuclear leakiness lead to transcriptional dysregulation and other intranuclear alterations lying upstream of β amyloid dysmetabolism? In this context, the paper by Hetzer's group could provide the foundation for a novel pathogenetic framework for AD. Finally, the implications of this study extend beyond the brain tor postmitotic cells in other organs such as the endocrine pancreas and for diseases associated with these cells including diabetes.
View all comments by John WoulfeSUNY Downstate Medical Center
Recent attention has been drawn to potential dysfunction of nuclear-cytoplasmic transport and the nuclear pore complex (NPC) in neurodegenerative disorders. In their intriguing report, Hetzer and colleagues used functional assays to demonstrate age-dependent deterioration of NPC. They found malfunction of a structural component of the NPC (Nup93) associated with increased nuclear permeability that was accelerated by reactive oxygen species. Their finding of nuclear accumulation of the cytoplasmic protein, tubulin, in aged rat neurons suggested that loss of nuclear integrity allows nuclear aggregation of cytoplasmic proteins.
In fact, abnormal transport may be bidirectional; nuclear transcription factors have been demonstrated in neuronal cytoplasm in Alzheimer disease and other common neurodegenerative disorders where they may influence abnormal protein aggregation. Together, the convergence of factors implicated in Hetzer's report, i.e., aging, nuclear integrity, abnormal protein aggregation, and oxidative stress, suggests a potential mechanism for neurodegeneration in human disease. Indeed, similar study of neurons in aged human brain and Alzheimer disease is warranted. If confirmed, the question as to whether this finding represents a key initiating event or is epiphenomenal would remain.
View all comments by Lynette G. SheffieldMake a Comment
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