Insight into protein synthesis in axon regeneration

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Insight into protein synthesis in axon regeneration

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https://doi.org/10.1016/j.expneurol.2023.114454Get rights and content

Abstract

Successful axon regeneration is crucial for the treatment of numerous nerve injuries and neurodegenerative diseases, which requires adequate and accurate protein synthesis, including mRNA translation, both in the neuron somas and locally in the axons. Recent studies have shed light on novel functions and mechanisms of protein synthesis that are relevant for axon regeneration, with a particular focus on local translation. Here, we review the new developed technologies and approaches for investigating local translation, discuss the roles of local translation in axon regeneration, and summarize the key signaling molecules and pathways that regulate local translation during axon regeneration. Additionally, we give an overview of local translation in the peripheral and central nervous systems neurons and the latest progress in protein synthesis in neuron somas respectively. Finally, we consider the potential directions for future research in this field to provide insights into protein synthesis in axon regeneration.

Introduction

Numerous disorders involving axon damage can benefit from successful axon regeneration, including stroke, traumatic brain injury, spinal cord injury, peripheral nerve injury, and a range of neurodegenerative diseases (Li et al., 2020; Qian and Zhou, 2020). As a complex and synergistic process involving multiple cellular events, axon regeneration requires the sustained activity of structural and regulatory proteins in both neuronal somas and axons (Rozenbaum et al., 2018; Terenzio et al., 2018; Zheng et al., 2001), implying that de novo protein synthesis in somas and axons is critical for axon regeneration in adult mammalian nervous systems (Belin et al., 2015; Donnelly et al., 2013; Weng et al., 2018). Due to technical constraints, it has long been believed that transcripts and their translational machinery are found in the dendrites of neurons but not in axons. Although polysomes have been found at the base of dendritic spines (Steward and Levy, 1982), mature axons typically exhibit low levels of ribosomes, which are primarily localized in periaxoplasmic ribosomal plaques (Calliari et al., 2014; Koenig et al., 2000; Sotelo-Silveira et al., 2008; Sotelo-Silveira et al., 2004). Thus, the prevalent view has been that axons are incapable of locally synthesizing proteins.

However, with methodological advances, it was eventually discovered that axon compartments contain a variety of RNA molecules, including ribosomal RNA, transfer RNA, and messenger RNA (Koenig, 1979; Koenig et al., 2000; Van Minnen, 1994; Weiner et al., 1996), suggesting protein synthesis in axons. The earliest direct evidence of local translation in mature mammalian axons came from sensory neurons in the peripheral nervous system (PNS). Zhang et al. separated pure regenerating axons from the dorsal root ganglion (DRG) cell bodies, and found that the axons can actively synthesize proteins (Zheng et al., 2001). Then numerous studies demonstrated that mature neurons in the central nervous system (CNS) can also synthesize proteins in their axons (Baleriola et al., 2014; Kalinski et al., 2015). And the local protein synthesis dynamically control the neuronal function in the CNS (Akins et al., 2017; Monday et al., 2022). In addition, studies have revealed that translation and ribosome biogenesis are rate-limiting processes for axon and dendrite growth (Slomnicki et al., 2016; Williams et al., 2016) and that the equilibrium of protein synthesis in the soma and axon influences axonal growth rates (Perry et al., 2016). These observations suggest that protein synthesis regulation at the levels of both axons and somas plays an important role in axon regeneration.

However, compared with transcriptional regulation, translational regulation in axon repair after injury is less understood. This emerging field is working toward the goal of revealing novel functions of protein synthesis in axon regeneration and identifying potential pharmacological targets in nerve injury or neurodegenerative diseases. Here, we will discuss these functions and provide a brief overview of the current understanding of the underlying mechanisms, including local translation and protein synthesis in the soma. Furthermore, we discuss what advancements in this field can be expected in the future.

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