This is an interesting paper with lots of data. The concept of NF-κB activation in senescence is relevant to neurodegenerative disorders.
For example, last year we reported that in individuals with mild cognitive impairment there was enhanced NF-κB activation with p65 detection in the nucleus of temporal lobe neurons (Ohta et al., 2014). Moreover, the p65 subunit of NF-κB was detectable in the nucleus of motor neurons from spinal cord samples of human ALS and of mice carrying human transgenes coding for ALS-linked TDP-43 mutants (Swarup et al., 2011, Figs 1 and 2). In these ALS mouse models, the NF-κB activation and neuroinflammation was age-dependent, occurring after 8 months of age when cytoplasmic accumulations of TDP-43 are detected.
In light of this paper by Kang et al., it would be of interest to determine if there is a correlation between levels of GATA4 and the appearance of cytoplasmic TDP-43 aggregates, a hallmark of ALS and FTLD.
References:
Ohta Y, Tremblay C, Schneider JA, Bennett DA, Calon F, Julien JP.
Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits.
Acta Neuropathol Commun. 2014 Apr 1;2:37.
PubMed.
Swarup V, Phaneuf D, Dupré N, Petri S, Strong M, Kriz J, Julien JP.
Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.
J Exp Med. 2011 Nov 21;208(12):2429-47.
PubMed.
Aging and aging-related neurodegenerative diseases are associated with signs of neuroinflammation. In this new study, Steve Elledge's laboratory in collaboration with Bruce Yankner’s laboratory provide evidence in support of a new molecular mechanism that links the DNA damage response with the senescence-associated secretory phenotype—including expression and secretion of pro-inflammatory cytokines, chemokines and proteases. The authors demonstrate accumulation of the transcription factor GATA4, which is thought to occur through the selective inhibition of autophagy by disrupting GATA4’s association with the autophagy adaptor protein, p62. Moreover, they report increased GATA4 levels in the astrocytes, pyramidal neurons, and oligodendrocytes of aged human frontal cortex in individuals who did not satisfy criteria for a neurodegenerative disease.
DNA damage accumulates with aging and is accelerated in brains with Alzheimer’s disease pathology. These exciting discoveries elucidate a new pathway to link DNA damage with neuroinflammation in the brains of presumed clinically normal aged individuals. These findings have important translational potential. Preventing or reversing the accumulation of GATA4 in the aging brain may offer therapeutic benefit by reducing the burden of neuroinflammation and thereby reducing the clinical manifestations of aging and neurodegenerative disease. However, outstanding questions still remain, including what the molecular mechanism of the disruption of the p62 and GATA4 association is, and how to harness this seemingly general mechanism in the appropriate cell type(s) in the nervous system. Also, when will a reliable biomarker for this mechanism be available to characterize the kinetics of this mechanism in the context of the disease spectrum of AD and to design clinical trials with intervention at the optimal stage of the disease?
Comments
This is an interesting paper with lots of data. The concept of NF-κB activation in senescence is relevant to neurodegenerative disorders.
For example, last year we reported that in individuals with mild cognitive impairment there was enhanced NF-κB activation with p65 detection in the nucleus of temporal lobe neurons (Ohta et al., 2014). Moreover, the p65 subunit of NF-κB was detectable in the nucleus of motor neurons from spinal cord samples of human ALS and of mice carrying human transgenes coding for ALS-linked TDP-43 mutants (Swarup et al., 2011, Figs 1 and 2). In these ALS mouse models, the NF-κB activation and neuroinflammation was age-dependent, occurring after 8 months of age when cytoplasmic accumulations of TDP-43 are detected.
In light of this paper by Kang et al., it would be of interest to determine if there is a correlation between levels of GATA4 and the appearance of cytoplasmic TDP-43 aggregates, a hallmark of ALS and FTLD.
References:
Ohta Y, Tremblay C, Schneider JA, Bennett DA, Calon F, Julien JP. Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits. Acta Neuropathol Commun. 2014 Apr 1;2:37. PubMed.
Swarup V, Phaneuf D, Dupré N, Petri S, Strong M, Kriz J, Julien JP. Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways. J Exp Med. 2011 Nov 21;208(12):2429-47. PubMed.
View all comments by Jean-Pierre JulienMassachusetts General Hospital
Aging and aging-related neurodegenerative diseases are associated with signs of neuroinflammation. In this new study, Steve Elledge's laboratory in collaboration with Bruce Yankner’s laboratory provide evidence in support of a new molecular mechanism that links the DNA damage response with the senescence-associated secretory phenotype—including expression and secretion of pro-inflammatory cytokines, chemokines and proteases. The authors demonstrate accumulation of the transcription factor GATA4, which is thought to occur through the selective inhibition of autophagy by disrupting GATA4’s association with the autophagy adaptor protein, p62. Moreover, they report increased GATA4 levels in the astrocytes, pyramidal neurons, and oligodendrocytes of aged human frontal cortex in individuals who did not satisfy criteria for a neurodegenerative disease.
DNA damage accumulates with aging and is accelerated in brains with Alzheimer’s disease pathology. These exciting discoveries elucidate a new pathway to link DNA damage with neuroinflammation in the brains of presumed clinically normal aged individuals. These findings have important translational potential. Preventing or reversing the accumulation of GATA4 in the aging brain may offer therapeutic benefit by reducing the burden of neuroinflammation and thereby reducing the clinical manifestations of aging and neurodegenerative disease. However, outstanding questions still remain, including what the molecular mechanism of the disruption of the p62 and GATA4 association is, and how to harness this seemingly general mechanism in the appropriate cell type(s) in the nervous system. Also, when will a reliable biomarker for this mechanism be available to characterize the kinetics of this mechanism in the context of the disease spectrum of AD and to design clinical trials with intervention at the optimal stage of the disease?
View all comments by Mark AlbersMake a Comment
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