Keeping synapses in shape: degradation pathways in the healthy and aging brain

Abstract

Synapses maintain their molecular composition, plasticity and function through the concerted action of protein synthesis and removal. The complex and polarized neuronal architecture poses specific challenges to the logistics of protein and organelle turnover since protein synthesis and degradation mainly happen in the cell soma. In addition, post-mitotic neurons accumulate damage over a lifetime, challenging neuronal degradative pathways and making them particularly susceptible to the effects of aging. This review will summarize the current knowledge on neuronal protein turnover mechanisms with a particular focus on the presynapse, including the proteasome, autophagy and the endolysosomal route and their roles in regulating presynaptic proteostasis and function. In addition, I will discuss how physiological brain aging, which entails a progressive decline in cognitive functions, affects synapses and the degradative machinery.

Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species

“…Autophagy activation has been already shown to protect against toxicity induced by Aβ, polyglutamine aggregates or overexpression of a mutant superoxide dismutase in the respective C. elegans disease models, namely AD [ 40 ], Huntington disease (HD) [ 58 ] and Amyotrophic Lateral Sclerosis (ALS) [ 59 ]. Interestingly, along with other degradation pathways, autophagy is involved in shaping up synaptic structure and function contributing to memory formation [ 60 , 61 ]. Most notably, synaptic alterations have been described in a few C. elegans studies during aging [ 62 , 63 ] (including the nAD strain used in this work— our unpublished observation ) and impairments of synaptic plasticity is an initial event underlying the memory loss and cognitive decline typically found in AD patients [ 64 – 67 ].…”

“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease

“…They rapidly fuse with a late endosome or lysosome, and subsequently retrograde transport along the axon to the cell body. This conserved mechanism plays an important role in the maintenance of synaptic homeostasis [ 67 , 68 ]. Specific deletion of Atg7 in Purkinje cells initially causes cell-autonomous progressive degeneration of the axon terminals with little sign of dendritic or spine atrophy, suggesting that axon terminals are much more vulnerable to autophagy impairment than dendrites [ 69 ].…”

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

“…Changes in neuronal wiring normally imply building up new synapses, however, they may occur without strong changes in neuronal morphology ( Bhatt et al, 2009 ). Both ultrastructural changes and de novo synaptogenesis are supported by protein synthesis, reorganization of cellular milieu, and degradation of cellular components ( Daskalaki et al, 2022 ; Kuijpers, 2022 ). As such, neuroplasticity implies a fine balance of ana- and cataplasticity that requires recycling and reutilization of macromolecules ( Liang and Sigrist, 2018 ; Nikoletopoulou and Tavernarakis, 2018 ; Liang, 2019 ).…”