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).
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
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- 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.