Proteostatic regulation in neuronal compartments

Abstract

Neurons continuously adapt to external cues and challenges, including stimulation, plasticity-inducing signals and aging. These adaptations are critical for neuronal physiology and extended survival. Proteostasis is the process by which cells adjust their protein content to achieve the specific protein repertoire necessary for cellular function. Due to their complex morphology and polarized nature, neurons possess unique proteostatic requirements. Proteostatic control in axons and dendrites must be implemented through regulation of protein synthesis and degradation in a decentralized fashion, but at the same time, it requires integration, at least in part, in the soma. Here, we discuss current understanding of neuronal proteostasis, as well as open questions and future directions requiring further exploration. The challenge of regulating a distant proteomeMost catalyzed chemical reactions inside cells depend on protein levels, and fine-tuning protein concentrations is key to ensure proper cellular function. Because throughout the cellular lifespan proteins accumulate damage, become dysfunctional and need to be replaced continually, protein synthesis and protein turnover are central to cellular physiology and function. The dynamic regulation of a balanced and functional proteome (i.e., proteostasis) concerns all proteins whose levels need to be adjusted in space and time in response to intracellular and extracellular cues. Thus, the specific parameters of cellular proteostasis vary across cell types and states. However, cellular proteostasis invariably relies on the precise control of protein synthesis, folding and conformational maintenance, post-translational modifications (PTMs), degradation, and secretion [1]. Precise control of these parameters is already challenging in cells that have little or no polarity, but becomes a particularly impressive feat for highly polarized cells, such as neurons.Neurons stand out from all other cell types in their unique morphology and high degree of compartmentalization; characteristics that are central to neuronal computation. Often, extrinsic signals are spatially localized so that only a confined portion of the neuron receives a certain signal, with the neuronal portion being, for instance, a cluster of dendrites (influenced by a neuromodulator), a single dendritic branch, a synaptic neighborhood, or even an individual synapse. How these local signals are transmitted to the somata remains largely unknown. Work over the last two decades has shown that neurons have the capacity to tune their proteome locally through regulation of local protein synthesis, degradation, and PTMs to regulate multiple aspects of dendritic and axonal biology [2]. Nevertheless, to date, we still lack a comprehensive understanding of how different cellular degradation pathways interact with the protein synthesis machinery to shape and maintain the local proteome.In this review, we discuss current understanding of neuronal local proteostatic regulation, and key knowledge gaps in the field. We also com...

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