Non-cell autonomous regulation of synaptic upscaling by neuronal autophagy

MARTA MAGLIONE (Freie Universität, Berlin)
STEPHAN J. SIGRIST (Freie Universität, Berlin)

Autophagy is an evolutionarily conserved cellular maintenance program, critical to protect the brain from premature ageing and neurodegeneration. How neuronal autophagy intersects with neuronal processes mediating brain maintenance and ageing remains to be explored. Using Drosophila, we previously showed that autophagy declines with ageing and that this is causally connected with a gain in size of presynaptic active zone scaffolds observed in a brain-wide fashion (“presynaptic upscaling”). These phenomena were associated with age-dependent memory impairment and supplementation with the endogenous autophagy-inducer spermidine protected from these age-related changes (Gupta et al., 2013, Nat neurosci; Gupta et al., 2016, Plos biology). In mice, spermidine restored ultrastructural changes and presynaptic plasticity at aged hippocampal mossy fiber synapses (Maglione et al., 2019, Sci Rep). Impairing autophagy solely in the Drosophila learning center (mushroom body, MB) triggered changes normally restricted to aged brains via the NPY-family neuropeptide sNPF (Bhukel et al., 2019, Nat commun). Several studies in mice highlighted NPY as a mediator of the beneficial effects exerted by caloric restriction and nutrient-sensing pathways via autophagy induction in hypothalamic neurons. This project addresses the likely bidirectional cross talk between neuronal autophagy and NPY/sNPF underlying presynaptic upscaling and memory function via cell autonomous and non-autonomous mechanisms in Drosophila (WP1) and mice (WP2), with the ultimate goal to provide basic knowledge for the development of anti-ageing interventions.

Gupta VK, Scheunemann L, Eisenberg T, … Madeo F & Sigrist SJ. (2013). Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci 16, 1453-1460.

Gupta VK, Pech U, Bhukel A, Fulterer A, … Maglione M, Quentin C, Bushow R, Schwärzel M, Mielke T, Madeo F, Dengjel J, Fiala A, & Sigrist SJ. (2016). Spermidine suppresses age-associated memory impairment by preventing adverse increase of presynaptic active zone size and release. PLoS Biol 14, e1002563.

Maglione M, Kochlamazashvili G, …Haucke V. Sigrist SJ. (2019). Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses. Sci Rep 9(1):19616

Bhukel A, Beuschel CB, Maglione M, Lehmann M, Juhasz G, Madeo F & Sigrist SJ. (2019). Autophagy within the mushroom body protects from synapse aging in a non-cell autonomous manner. Nat Commun 10, 1318.