Shukla AK, Spurrier J, Kuzina I, Giniger E.
Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5.
Cell Rep. 2019 Jan 2;26(1):131-144.e4.
PubMed.
This is not surprising, as we and others have shown that an over-reactive immune response is toxic to the fly’s neuronal cells in an age-dependent manner. In fact, silencing NF-κΒ-mediated immunity in glia in both flies (Kounatidis et al., 2017) and mice (Zhang et al., 2013) from the start of life, extends lifespan dramatically.
The connection of immunity to CDK5 via autophagy is novel and interesting. From a fly perspective one might speculate that, normally, the pathway culminating in the action of the Drosophila NF-kβ ortholog Relish, is occupied by an autophagy connection where one component of the pathway’s Ikβ-kinase (IKKγ or Kenny) is interacting with Atg8 to promote the autophagic degradation of the Ikβ-kinase, thus preventing activation without reason (see Tusco et al., 2017). However, when autophagy is blocked, then Ikβ-kinase is free to activate Relish. From the Giniger paper, it is unclear what are the molecular events, direct or indirect, that mediate blocking of V-ATP, lysosomal function, and autophagic flux in the cdk5 mutants.
From a human perspective, it seems that inflammation and an overactive immunity might be an evolutionary conserved etiology for a number of neurodegenerative diseases (NDs). Therefore anti-inflammatory drugs might be appropriate candidates. However, although genome-wide association studies have implicated innate immunity in the etiology of NDs, it is not clear whether predisposition to an overactive innate immunity or an early inability to respond to an inflammatory environment is at the start of the chain of events leading to age-dependent neurological disease. More work, especially in model systems where one can do easy genetic manipulations to get to the ground state, is needed to arrive at causality.
References:
Kounatidis I, Chtarbanova S, Cao Y, Hayne M, Jayanth D, Ganetzky B, Ligoxygakis P.
NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration.
Cell Rep. 2017 Apr 25;19(4):836-848.
PubMed.
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D.
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.
Nature. 2013 May 1;
PubMed.
Tusco R, Jacomin AC, Jain A, Penman BS, Larsen KB, Johansen T, Nezis IP.
Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses.
Nat Commun. 2017 Nov 2;8(1):1264.
PubMed.
In this study, Shukla, Giniger and colleagues use fly genetics to show dysregulation of Cdk5 activity causes disruption of autophagy, a hyperactive innate immune response, and neurodegeneration of dopamine neurons in Drosophila. They elegantly demonstrate a hyperactive innate immune response is sufficient to cause neuronal cell death.
Intriguingly, they show that blocking the NF-κB transcription factor in neurons downregulates innate immune response genes and reduces neuronal loss in the Cdk5 null background. These are important observations providing mechanistic insight into the cascade of events leading to neurodegeneration.
It would be interesting to know if the mechanism underlying neurodegeneration caused by Cdk5 dysregulation is conserved in the mammalian system. Moreover, as hyperactivation of Cdk5 is associated with various neurodegenerative conditions in mammals, it would be important to know if there are other mechanisms beyond disruption of autophagy that mediate these neurodegenerative conditions.
Comments
University of Oxford
This is not surprising, as we and others have shown that an over-reactive immune response is toxic to the fly’s neuronal cells in an age-dependent manner. In fact, silencing NF-κΒ-mediated immunity in glia in both flies (Kounatidis et al., 2017) and mice (Zhang et al., 2013) from the start of life, extends lifespan dramatically.
The connection of immunity to CDK5 via autophagy is novel and interesting. From a fly perspective one might speculate that, normally, the pathway culminating in the action of the Drosophila NF-kβ ortholog Relish, is occupied by an autophagy connection where one component of the pathway’s Ikβ-kinase (IKKγ or Kenny) is interacting with Atg8 to promote the autophagic degradation of the Ikβ-kinase, thus preventing activation without reason (see Tusco et al., 2017). However, when autophagy is blocked, then Ikβ-kinase is free to activate Relish. From the Giniger paper, it is unclear what are the molecular events, direct or indirect, that mediate blocking of V-ATP, lysosomal function, and autophagic flux in the cdk5 mutants.
From a human perspective, it seems that inflammation and an overactive immunity might be an evolutionary conserved etiology for a number of neurodegenerative diseases (NDs). Therefore anti-inflammatory drugs might be appropriate candidates. However, although genome-wide association studies have implicated innate immunity in the etiology of NDs, it is not clear whether predisposition to an overactive innate immunity or an early inability to respond to an inflammatory environment is at the start of the chain of events leading to age-dependent neurological disease. More work, especially in model systems where one can do easy genetic manipulations to get to the ground state, is needed to arrive at causality.
References:
Kounatidis I, Chtarbanova S, Cao Y, Hayne M, Jayanth D, Ganetzky B, Ligoxygakis P. NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration. Cell Rep. 2017 Apr 25;19(4):836-848. PubMed.
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013 May 1; PubMed.
Tusco R, Jacomin AC, Jain A, Penman BS, Larsen KB, Johansen T, Nezis IP. Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses. Nat Commun. 2017 Nov 2;8(1):1264. PubMed.
View all comments by Petros LigoxygakisPicower Institute of MIT
In this study, Shukla, Giniger and colleagues use fly genetics to show dysregulation of Cdk5 activity causes disruption of autophagy, a hyperactive innate immune response, and neurodegeneration of dopamine neurons in Drosophila. They elegantly demonstrate a hyperactive innate immune response is sufficient to cause neuronal cell death.
Intriguingly, they show that blocking the NF-κB transcription factor in neurons downregulates innate immune response genes and reduces neuronal loss in the Cdk5 null background. These are important observations providing mechanistic insight into the cascade of events leading to neurodegeneration.
It would be interesting to know if the mechanism underlying neurodegeneration caused by Cdk5 dysregulation is conserved in the mammalian system. Moreover, as hyperactivation of Cdk5 is associated with various neurodegenerative conditions in mammals, it would be important to know if there are other mechanisms beyond disruption of autophagy that mediate these neurodegenerative conditions.
View all comments by Li-Huei TsaiMake a Comment
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