An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection

Abstract

In Brief E et al. reveal an unexpected function of antimicrobial peptides as the signal molecule to trigger aging-and infectionassociated dendrite degeneration and show that an epidermally expressed antimicrobial peptide can activate a conserved neuronal GPCR to cause dendrite degeneration through autophagic machinery. E et al., 2018, Neuron 97, 125- SUMMARYInfections have been identified as possible risk factors for aging-related neurodegenerative diseases, but it remains unclear whether infection-related immune molecules have a causative role in neurodegeneration during aging. Here, we reveal an unexpected role of an epidermally expressed antimicrobial peptide, NLP-29 (neuropeptide-like protein 29), in triggering aging-associated dendrite degeneration in C. elegans. The age-dependent increase of nlp-29 expression is regulated by the epidermal tir-1/ SARM-pmk-1/p38 MAPK innate immunity pathway. We further identify an orphan G protein-coupled receptor NPR-12 (neuropeptide receptor 12) acting in neurons as a receptor for NLP-29 and demonstrate that the autophagic machinery is involved cell autonomously downstream of NPR-12 to transduce degeneration signals. Finally, we show that fungal infections cause dendrite degeneration using a similar mechanism as in aging, through NLP-29, NPR-12, and autophagy. Our findings reveal an important causative role of antimicrobial peptides, their neuronal receptors, and the autophagy pathway in aging-and infection-associated dendrite degeneration.

Caenorhabditis elegansExhibits Positive Gravitaxis

“…Some of this deterioration is identifiable with specific neuronal deficits. For example, the sensory dendrites of the FLP and PVD neurons, which are required for response to certain mechanical stimuli, degenerate with age (19). To examine aging worms’ ability to sense and orient in gravitational field, we measured the angle of descent as a function of animal’s age (Fig.…”

Does senescence promote fitness in Caenorhabditis elegans by causing death?

“…Supporting this possibility, under laboratory conditions proteostatic collapse reduces heat shock resistance within hours of reproductive maturity ( Labbadia and Morimoto, 2015 ); impairment of proteostasis due to loss of the HSF-1 transcription factor increases susceptibility to a range of bacterial pathogens ( Singh and Aballay, 2006 ); and blocking germline development, which inhibits proteostatic collapse ( Labbadia and Morimoto, 2015 ), also increases resistance to bacterial and fungal pathogens ( Alper et al, 2010 ; TeKippe and Aballay, 2010 ). Here it is also notable that the fungal pathogen Drechmeria coniospora causes NLP-29-dependent acceleration of PVD neurite degeneration in early adulthood ( E et al, 2018 ). If senescence causes significant increases in adult mortality rate soon after reproductive maturity, then consumer sacrifice is no longer ruled out, and the objections from the infinite petri dish scenario may be dismissed.…”

“…Since the discovery of proteostatic collapse in 2009, more studies have appeared documenting other examples of early deterioration in C. elegans . For example, long-term memory is impaired by days 2–3 of adulthood and is entirely lost by day 5 ( Kauffman et al, 2010 ), and degeneration of the dendrites of PVD neurons occurs from ∼day 4–7 that is actively promoted by the antimicrobial peptide NLP-29 and driven by autophagy ( E et al, 2018 ). Also, in early adulthood C. elegans neurons extrude membrane-bound vesicles full of aggregated proteins and organelles (exophers), suggesting pathological upheaval at this time ( Melentijevic et al, 2017 ).…”

Modulatory upregulation of an insulin peptide gene by different pathogens in C. elegans

“…A number have been characterized in the context of the response of C. elegans to biotic and abiotic insults (reviewed in [ 5 ]). To give one recent example, activation of a conserved p38 MAPK pathway in the intestine by rotenone is associated with protection from neurodegeneration [ 6 ], conceivably because induction of the mitochondrial unfolded protein response in the intestine represses the expression of the antimicrobial peptide gene nlp-29 [ 7 ], which regulates dendrite degeneration in aging and infection [ 8 ]. But, as is commonly the case, the molecular nature of the signal mediating this cross-tissue control has not yet been established.…”