Autophagy, Inflammation, Degeneration: Parsing an Unholy Trinity

In neurodegenerative disease, inflammation runs rampant in the brain. But is this a cause or a consequence of pathology? Researchers led by Edward Giniger at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, argue in the January 2 Cell Reports that neuroinflammation causes degeneration, at least in a model. Flies with either too much or too little cyclin-dependent kinase 5 (Cdk5) lose neurons as they age. The scientists traced the cause to weakened autophagy in neurons, which in turn unleashed a massive inflammatory response that accelerated age-related neuron loss.

  • Flies with perturbed Cdk5 lose neurons with age.
  • It starts with weakened autophagy, which unleashes inflammation.
  • Restoring autophagy or inflammation to normal saved neurons.

“This clarifies the roles and relationships of three of the major features of neurodegenerative disease: aging, immunity, and autophagy,” Giniger told Alzforum. He noted that the genes and interactions he studied in flies all exist in people and have been linked to neurodegenerative disease. “It is extremely likely that the cascade of events we see in the fly also acts in humans,” Giniger said. He believes the cascade offers a starting point for investigating therapies to slow disease progression.

Petros Ligoxygakis at the University of Oxford, U.K., found the data intriguing. “The connection of immunity to Cdk5 via autophagy is novel and interesting,” he wrote to Alzforum. However, he noted that more research is needed to determine whether the initiating event in human pathology is an immune response that is too strong or too weak (full comment below).

Neurodegenerative Cascade? Research in flies ties aspects of neurodegenerative disease into one pathway. [Courtesy of Cell Reports, Shukla et al.]

Unlike other cyclin-dependent kinases, Cdk5 plays no role in the cell cycle. It activates when it binds the Cdk5α subunit, which occurs only in postmitotic neurons. Cdk5 has been tied to memory, neurogenesis, tau phosphorylation, and neurodegeneration (Mar 2014 news; Nov 2008 news; May 2003 news). 

Giniger and colleagues previously characterized Drosophila lines that lacked Cdk5α or overexpressed it threefold. With age, both models developed movement problems and lost mushroom body neurons, which handle fly learning and memory. They also aged faster than wild-type flies, with age-related gene expression changing at double the wild-type rate in some tissues (Spurrier et al., 2018). 

Since then, the authors have noticed that the mutants’ gene-expression profile resembled that of a fly model of Parkinson’s disease (Park et al., 2006). This led first author Arvind Shukla to examine dopaminergic neurons in the Cdk5 mutants. In wild-type flies, dopaminergic neurons start dying near the end of the lifespan, at 45 days, but Cdk5α-null flies lost them starting on the third day of life, and overexpressers by day 30.

Did these neurons just age faster, or were other processes at work? The authors found gene-expression changes in the mutants that correlated not with age, but instead with the severity of neurodegeneration. Nearly half of these were innate immunity genes. They included antimicrobial peptides (AMPs), secreted factors that fight invading pathogens. In Cdk5 mutant flies, AMP levels in neurons surged with age, surpassing levels in age-matched controls by as much as 100-fold. “That this expression happened in neurons themselves, rather than immune cells, was a big surprise to us,” Giniger noted.

What does this massive immune response do? When the researchers suppressed it by crossing the Cdk5 mutants to flies lacking a crucial transcription factor, AMP levels dropped and dopaminergic neurons survived as well as they did in wild-type. Conversely, overexpressing individual AMPs in flies accelerated neuron loss, implying that inflammation causes degeneration.

But how might Cdk5 affect inflammation? Perturbed Cdk5 is known to disrupt autophagy, which in turn can stimulate the innate immune response (Trunova and Giniger, 2012; Wu et al., 2007). Was this the connection? In keeping with this hypothesis, the authors saw autophagic flux slow to a trickle in dopaminergic neurons of the Cdk5 mutants (see image above). When they stimulated autophagy in the flies, neurons made fewer AMPs and more dopaminergic neurons survived. Curtailing autophagy further, however, did the opposite, boosting AMP production and speeding up neuron loss.

To Giniger’s mind, the data suggest a pathway to degeneration. “There is a cascade where defective autophagy hyperstimulates immunity, hyperimmunity kills neurons, and this specific insult acts synergistically with the general fragility of aging to produce the overall effects of disease,” he proposed.

How does Cdk5 impair autophagy? It’s unclear. Likewise, how autophagy affects immunity needs clarification. Ligoxygakis noted that innate immune responses in Drosophila are kept in check by autophagic degradation of a key effector molecule, Ikβ-kinase (Tusco et al., 2017). Defective autophagy would remove this brake, perhaps enabling the runaway response the authors saw.

If this pathway is conserved in humans, what diseases might it trigger? Giniger believes Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis/frontotemporal dementia are all candidates. He is surveying the effect of altered Cdk5 activity on different neuron types in the mutant flies to define the extent of neurodegeneration. The mammalian ortholog of Cdk5a, p35, triggers AD-like pathology in mice (Mar 2012 news; Apr 2010 news). Other studies link it to PD and ALS (Smith et al., 2003; Nguyen et al., 2001).—Madolyn Bowman Rogers

Comments

  1. 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 Ligoxygakis

  2. 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 Tsai

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References

News Citations

  1. Cdk5 Controls Memory Switch in Neurons
  2. Jack of All Trades? Cdk5 Implicated in Neurotransmission, Neurogenesis
  3. Aiding and Abetting, Hyperactive CDK5 Gives Mouse Tangles
  4. Does Epigenetic Modification by Aβ Offer New Take on Therapy?
  5. Cdk5—Novel Brake on the Cell Cycle, Implications for AD?

Paper Citations

  1. Spurrier J, Shukla AK, McLinden K, Johnson K, Giniger E. Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging. Dis Model Mech. 2018 Mar 8;11(3) PubMed.
  2. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006 Jun 29;441(7097):1157-61. PubMed.
  3. Trunova S, Giniger E. Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila. Dis Model Mech. 2012 Mar;5(2):210-9. PubMed.
  4. Wu J, Randle KE, Wu LP. ird1 is a Vps15 homologue important for antibacterial immune responses in Drosophila. Cell Microbiol. 2007 Apr;9(4):1073-85. Epub 2006 Dec 12 PubMed.
  5. 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.
  6. Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, O'Hare MJ, Callaghan S, Slack RS, Przedborski S, Anisman H, Park DS. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13650-5. PubMed.
  7. Nguyen MD, Larivière RC, Julien JP. Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron. 2001 Apr;30(1):135-47. PubMed.

Further Reading

Primary Papers

  1. 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.

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