Autophagy within the mushroom body protects from synapse aging in a non-cell autonomous manner

Abstract

Macroautophagy is an evolutionarily conserved cellular maintenance program, meant to protect the brain from premature aging and neurodegeneration. How neuronal autophagy, usually loosing efficacy with age, intersects with neuronal processes mediating brain maintenance remains to be explored. Here, we show that impairing autophagy in the Drosophila learning center (mushroom body, MB) but not in other brain regions triggered changes normally restricted to aged brains: impaired associative olfactory memory as well as a brain-wide ultrastructural increase of presynaptic active zones (metaplasticity), a state non-compatible with memory formation. Mechanistically, decreasing autophagy within the MBs reduced expression of an NPY-family neuropeptide, and interfering with autocrine NPY signaling of the MBs provoked similar brain-wide metaplastic changes. Our results in an exemplary fashion show that autophagy-regulated signaling emanating from a higher brain integration center can execute high-level control over other brain regions to steer life-strategy decisions such as whether or not to form memories.

On the Fly: Recent Progress on Autophagy and Aging in Drosophila

“…A typical symptom of aging is memory loss, and a recent study reported that autophagy affects memory function in flies (Bhukel et al, 2019). Impaired autophagy due to silencing of Atg5 or Atg9 in the learning center (mushroom body) of the Drosophila brain attenuates associative olfactory memory and decreases the level of neuropeptide Y, which normally acts non-cell-autonomously to promote memory function.…”

Autophagy and the endolysosomal system in presynaptic function

“…Synaptic neurotransmission comes along with huge metabolic demands [3,4], elevated rates of protein turnover [5] and high membrane exchange that imposes significant challenges for the efficient delivery and constant supply of newly synthesized proteins. Likewise, removal of damaged proteins and organelles from synaptic sites and, in particular, from presynaptic boutons is essential to sustain synaptic function [6][7][8]. In addition, synapses are subject of activity-induced changes in their proteinaceous composition that underlie plastic processes in the context of learning and memory and that further exacerbate the complexity of local proteostasis [9][10][11].…”

Balanced actions of protein synthesis and degradation in memory formation

“…As discussed earlier, autophagy is induced by learning stimuli and is required for memory formation (Glatigny et al 2019); however, reduced autophagy biogenesis and reduced expression of autophagy essential genes were found to be correlated with age-related memory decline (Rubinsztein et al 2011;Stavoe and Holzbaur 2018). Consistently, selective impairment of autophagy in the Drosophila mushroom body produced similar alterations of associative olfactory memory, neuronal structures, and neuropeptide signaling (Bhukel et al 2019). Boosting autophagy levels in the hippocampus of the aged mice was sufficient for reversing memory deficits (Glatigny et al 2019), suggesting that memory impairment can be restored by manipulating the autophagy levels.…”