Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Abstract

Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.

Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination

“…We (e.g. Minerbi et al, 2009; Hazan and Ziv, 2020) and others (Saalfrank et al, 2015) have found that under these conditions, neurons in culture are much more viable and resilient to insults such as pharmacological suppression of protein synthesis (Cohen et al, 2022). Indeed, in a separate set of experiments carried out on neurons maintained in small volumes in an incubator (i.e., without perfusion) and stained against Microtubule Associated Protein 2 (MAP2; somatodendritic compartments) and Neuro lament-heavy chain (axons), a shift toward a somatodendritic localization was observed, including aggregates within nuclei (Supp.…”

Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases

“…The structural integrity and functional properties of synapses further depend on continuous protein renewal, which in turn depends on the rate-limiting steps in protein synthesis [25]. Xu et al (2020) examined the eukaryotic translation initiation factor 4E (eIF4E) involved in the rate-limiting step in protein synthesis using a transgenic mouse model of ASD [14].…”

The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis

“…A potential mechanism by which translational inhibitors might suppress neural signaling would be through mitochondrial poisoning (Cohen et al, 2022, p. 113; Scavuzzo et al, 2019, p. 50). In eukaryotic cells, mitochondrial function is dependent on nuclear‐derived proteins, despite independent protein synthesis in mitochondria themselves (Dudek, 2013, p. 115).…”