Separating the roles of autophagy, immunity and aging in neurodegeneration
Arvind Shukla, Joshua Spurrier and Edward Giniger NINDS, NIH (USA)
Neurodegeneration is associated with changes in innate immunity, but four core problems evade us:
How do we rule out that correlations between immune function and neurodegeneration are simply secondary to aging?
Does immune dysfunction cause degeneration, or is altered immunity a response to tissue stress?
Does degeneration arise from an excessive immune response, or an insufficient one?
What mechanism causes alteration of immunity during degeneration?
We now answer all of these questions in a Drosophila model of neurodegeneration, altered activity of the fly ortholog of the tau kinase, Cdk5/p35.
First, we separate immunity from the effects of aging. We recently published a rigorous quantitative metric for physiological age based on expression profiling. Applying this metric to our model of degeneration demonstrates that acceleration of the absolute rate of aging is one component of the mechanism of degeneration. This analysis, however, also isolates a non-aging component, and shows it is dominated by hyperactivation of the innate immune response, particularly anti-microbial peptides (AMPs). We show that AMP activation occurs early in the degeneration cascade, and that it is both necessary and sufficient to lead to death of dopamine neurons, separate from the effects of aging. This shows that it is hyperactivity of immunity that is pathogenic, not insufficiency; that activation of immunity is cause and not consequence of cell loss, and that it acts in parallel to the effects of age.
Next, we show that disruption of autophagy is a causal trigger for activation of immunity. Altered activity of Cdk5/p35 blocks autophagic flux. We find that blocking autophagy by another method is sufficient to hyperactivate AMP expression and lead to loss of dopamine neurons, while overexpression of an activator of autophagy (MITF) in a mutant lacking Cdk5 activity restores autophagy, blocks AMP overexpression and restores survival of dopamine neurons.
These data provide compelling evidence that hyperactivation of the innate immune response cooperates with acceleration of aging to cause loss of dopamine neurons in a Drosophila model of neurodegeneration, and that this immune activation occurs as a consequence of disrupted autophagy. We suggest that this mechanism is also likely to play a central role in human disease.
Credits: None available.
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