Mechanism of synaptic protein turnover and its regulation by neuronal activity

https://doi.org/10.1016/j.conb.2021.02.006Get rights and content

Highlights

  • Synaptic protein turnover is regulated by neuronal activity and other factors.

  • Multiple systems cooperate to control synaptic proteostasis.

  • Neuronal autophagy impacts on synaptic function.

  • Lysosomes may degrade synaptic proteins locally or in somata.

  • Ubiquitin serves as a common degradation signal for ubiquitin–proteasome system and lysosomes.

Abstract

Neurons are long-lived cells with a complex architecture, in which synapses may be located far away from the cell body and are subject to plastic changes, thereby posing special challenges to the systems that maintain and dynamically regulate the synaptic proteome. These mechanisms include neuronal autophagy and the endolysosome pathway, as well as the ubiquitin/proteasome system, which cooperate in the constitutive and regulated turnover of presynaptic and postsynaptic proteins. Here, we summarize the pathways involved in synaptic protein degradation and the mechanisms underlying their regulation, for example, by neuronal activity, with an emphasis on the presynaptic compartment and outline perspectives for future research. Keywords: Synapse, Synaptic vesicle, Autophagy, Endolysosome, Proteasome, Protein turnover, Protein degradation, Endosome, Lysosome

Introduction

Protein components (i.e. amino acids) need to be recycled to produce new materials. In addition, proteins can be misfolded or damaged as a consequence of oxidative stress, disease, or aging or be dispensable for function at a given time or place. Protein turnover is therefore essential for maintaining healthy and functional cells. This is of particular importance for neurons, for example, long-lived cells with a highly polarized architecture and complex morphology that present special challenges with respect to the machineries that spatiotemporally regulate protein turnover, as synapses can be located far away from the cell body where the majority of degradative processes take place [1, 2, 3]. To maintain and plastically regulate neurotransmission, a process that involves presynaptic neurotransmitter release by synaptic vesicle (SV) fusion and recognition of neurotransmitter molecules by postsynaptic receptors and their associated factors, synaptic proteins have to be turned over [4].

Actively releasing SVs have a finite lifetime, and aging vesicles get inactivated and eventually degraded [5]. As protein degradation is essential for the remodeling of synapses and for synaptic plasticity [6], synaptic protein turnover is expected to be regulated by synaptic activity. Indeed, experiments in neuronal cultures show that the turnover of presynaptic vesicle proteins is facilitated by increased neuronal activity. Conversely, synaptic protein synthesis and degradation decrease in response to suppression of activity [5, 6∗, 7]. Moreover, experience-dependent synaptic plasticity in mice accelerates the turnover of the majority of synaptic proteins [7].

In this review, we will summarize three pathways involved in synaptic protein degradation, that is, autophagy, the endolysosomal pathway, and the proteasome system. We discuss the mechanisms underlying their regulation, for example, by neuronal activity and mechanistic target of rapamycin (mTOR) with emphasis on the presynaptic and axonal compartments.

Section snippets

Neuronal protein turnover in vitro and in vivo

Recent methodological advances, for example, combining stable isotope labeling of proteins with mass spectrometry, have enabled high-throughput analysis of protein lifetimes. Such studies show that the rate of protein turnover depends on protein function, protein complex architecture, and subcellular localization, as well as on the neuronal cell type and environment [7, 8, 9]. As protein turnover appears to be essential for the regulation of neuronal activity and for synapse remodeling [10],

Neuronal autophagy

Recent work in many systems including neurons have established crucial roles for autophagy in the regulation of protein turnover and for the maintenance of neuronal health [16,17]. Although often used synonymously, there are at least three distinct types of autophagy, that is, microautophagy, chaperone-mediated autophagy, and macroautophagy. While morphologically and mechanistically distinct, all three culminate in the delivery of cargo to the lysosome. Microautophagy is defined by the uptake

Endolysosomal turnover of presynaptic proteins

In addition to autophagy, the turnover of synaptic proteins and maintenance of synaptic transmission depend on the endolysosomal pathway. While little is known about the role of the endolysosomal system in the turnover of postsynaptic proteins, previous data in cultured neurons suggest that SV proteins at the presynapse are subject to quality control [31,36] via mechanisms involving ubiquitination and sorting into late endosomes via the endosomal sorting complex required for transport (ESCRT)

Control of synaptic proteostasis by the ubiquitin–proteasome system and mTOR

In addition to autophagy and the endolysosomal system, which are mostly responsible for the turnover of membrane proteins and large protein assemblies including entire organelles, most cytoplasmic proteins including axoplasmic and dendritic proteins are degraded by the ubiquitin–proteasome system (UPS) [43]. Although protein breakdown via these two pathways takes place in distinct subcellular locations and uses different degradative enzymes, the UPS and lysosomal degradation systems share some

Conclusion and perspectives

While we have gained substantial new insights in recent years into the mechanisms and machineries involved in synaptic protein turnover, many fundamental questions remain unsolved. For example, we still do not understand how presynaptic and postsynaptic proteins are tagged for degradation and how an aged defective synaptic protein is distinguished molecularly from its young functional counterpart. We also do not know whether the components of synaptic organelles such as SVs are degraded in toto

Conflict of interest statement

Nothing declared.

Acknowledgements

The authors thank Dr. Barth van Rossum (FMP, Berlin) for help with the artwork. Our own research was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) [HA 2686/13–1 to V.H.], the Neurocure Cluster of Excellence (DFG-Exc-257), the German Ministry of Science (BMBF; SMARTAGE, to V.H.), and a postdoctoral fellowship of the European Union (to M.K.).

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