RNA-Binding Proteins and Translation in Neurodegenerative Disease

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

The Integrated Stress Response in Memory and Cognitive Disorders

The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that responds to proteostasis defects and stress conditions by tuning protein synthesis rates. While it has been long recognized that long-term memory formation requires new protein synthesis, our understanding of the central translational control mechanisms that regulate memory formation has advanced vastly. Indeed, novel causal and convergent evidence across different species and model systems shows that the ISR serves as a universal regulator of long-term memory formation. This chapter discusses the evidence explaining how inhibition of the ISR enhances long-term memory formation while activation of the ISR prevents it. In addition, it highlights the role of the ISR in different forms of long-lasting synaptic plasticity in the brain. Finally, the chapter addresses how dysregulated ISR signaling contributes to the pathogenesis of a wide range of cognitive and neurodegenerative disorders and discusses the future prospects for therapeutically targeting the ISR for the treatment of cognitive disorders.

RNA Modifications in the Central Nervous System

Epitranscriptomics, a recently emerged field to investigate post-transcriptional regulation of gene expression through enzyme-mediated RNA modifications, is rapidly evolving and integrating with neuroscience. Using a rich repertoire of modified nucleosides and strategically positioning them to the functionally important and evolutionarily conserved regions of the RNA, epitranscriptomics dictates RNA-mediated cell function. The new field is quickly changing our view of the genetic geography in the brain during development and plasticity, impacting major functions from cortical neurogenesis, circadian rhythm, learning and memory, to reward, addiction, stress, stroke, and spinal injury, etc. Thus understanding the molecular components and operational rules of this pathway is becoming a key for us to decipher the genetic code for brain development, function, and disease. What RNA modifications are expressed in the brain? What RNAs carry them and rely on them for function? Are they dynamically regulated? How are they regulated and how do they contribute to gene expression regulation and brain function? This chapter summarizes recent advances that are beginning to answer these questions.

Focusing on mRNA Granules and Stalled Polysomes Amidst Diverse Mechanisms Underlying mRNA Transport, mRNA Storage, and Local Translation

In neurons, mRNAs are transported to distal sites to allow for localized protein synthesis. There are many diverse mechanisms underlying this transport. For example, an individual mRNA can be transported in an RNA transport particle that is tailored to the individual mRNA and its associated binding proteins. In contrast, some mRNAs are transported in liquid-liquid phase separated structures called neuronal RNA granules that are made up of multiple stalled polysomes, allowing for rapid initiation-independent production of proteins required for synaptic plasticity. Moreover, neurons have additional types of liquid-liquid phase–separated structures containing mRNA, such as stress granules and P bodies. This chapter discusses the relationships between all of these structures, what proteins distinguish them, and the possible roles they play in the complex control of mRNA translation at distal sites that allow neurons to use protein synthesis to refine their local proteome in many different ways.

Multiple Roles of RNA Regulatory Factors in Neuronal Development and Function in C. elegans

Recent evidence has highlighted the dynamic nature of mRNA regulation, particularly in the nervous system, from complex pre-mRNA processing to long-range transport and long-term storage of mature mRNAs. In accordance with the importance for mRNA-mediated regulation of nervous system development and maintenance, various mutations in RNA-binding proteins are associated with a range of human disorders. C. elegans express many RNA-binding factors that have human orthologs and perform similar biochemical functions. This chapter focuses on the research using C. elegans to dissect molecular mechanisms involving mRNA-mediated pathways. It highlights the key approaches and findings that integrate genetic and genomic studies in the nervous system. The analyses of genetic mutants, primarily using forward genetics, offer functional insights for genes important for neuronal development, synaptic transmission, and neuronal repair. In combination with single-neuron cell biology and cell-type genomics, the knowledge learned from this model organism has continued to lead to ground-breaking discoveries.

Regulation of Protein Synthesis by eIF4E in the Brain

Regulation of gene expression at the level of mRNA translation is crucial for all the functions our brains carry out. eIF4E binds to the 5′-end of eukaryotic mRNAs and dictates the rate-limiting step of cap-dependent initiation. This chapter reviews the key pathways regulating eIF4E function, but also the less studied and novel mechanisms of eIF4E modulation, linked to synaptic plasticity, learning and memory, and nervous system disorders. Understanding how regulation of protein synthesis by eIF4E affects different aspects of brain function is yet elusive.

Role of CPEB-Family Proteins in Memory

A synapse-based mechanism of formation and persistence of long-term memory (LTM) entails some unique mechanistic challenges. It requires experience-dependent changes in synapse composition, function, and number. These changes must be specific to the synapse of interest, although all synapses in a neuron rely on the same genome. Finally, these changes must persist over time in the face of constant synaptic protein turnover. It has long been known that translation at the synapse is one of the fundamental requirements for LTM, and multiple mechanisms of synaptic translation have been characterized. Among these translation regulatory mechanisms, cytoplasmic polyadenylation element binding protein (CPEB) family members fulfill some of the unique needs of LTM and can even be considered as contributing to the biochemical substrates of memory. These proteins orchestrate a “synaptic mark” and regulate translation of specific mRNAs required for changes in synaptic composition, function, and number. Some CPEB family members also self-assemble and alter their function to maintain the altered synaptic state over time, contributing to persistence of memory. This chapter summarizes the known function of different CPEB family members in memory, their underlying molecular mechanisms, and important issues that remain to be resolved.

The Role of the Eukaryotic Elongation Factor 2 (eEF2) Pathway in Neuronal Function

In the brain, mRNA translation regulation plays a major role during different processes, including development, learning and memory, and synaptic plasticity. While the initiation phase of translation is considered to be the rate-limiting step, regulation of the elongation phase via the eukaryotic elongation factor 2 kinase (eEF2K) pathway is also pivotal for memory and synaptic plasticity consolidation. Understanding the molecular mechanisms underpinning memory and synaptic plasticity formation is invaluable for understanding basic mechanisms underlying cognitive function and the identification of effective targets for cognitive disorders. This chapter discusses the molecular function of the eEF2/eEF2K pathway in memory consolidation, synaptic plasticity, and neurological diseases. In addition, it describes possible new genetic tools that would be useful in determining the neuronal function of eEF2K in health and disease conditions.

Regulation of mRNA Translation in Axons

Axons can extend long distances from the neuronal cell body, and mRNA translation in axons is used to locally generate new proteins in these distal reaches of the neuron’s cytoplasm. Work over the past two decades has shown that axonal mRNA translation occurs in many different organisms and different neuronal systems. The field has progressed substantially over this time, moving from documenting mRNA translation in axons to understanding how axonal mRNA translation is regulated and what the protein products do for the neuron. Translational regulation in axons extends beyond merely controlling activity of the protein synthesis machinery. Transport of mRNAs into axons, stability of the mRNAs within the axons, and sequestration of mRNAs away from the translational machinery each contribute to determining what proteins are generated in axons, as well as when and where those proteins are generated within the axon. It is now known that thousands of different mRNAs can localize into axons. Based on unique responses to different axonal translation regulating stimuli and events, there clearly is specificity for when different mRNA populations are translated. How that specificity is driven is just now beginning to be understood, and studies emerging over the last five years point to multiple mechanisms for imparting specificity for regulation of axonal protein synthesis responses.

Dysregulated Translation in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex genetic architecture and heterogeneous symptomatology. Increasing evidence indicates that dysregulated brain protein synthesis is a common pathogenic pathway involved in ASD. Understanding how genetic variants converge on a common molecular signaling pathway in neurons and brain circuits, resulting in ASD-relevant synaptic and behavioral phenotypes, is of great interest in the autism research community. This article focuses on ASD-risk genes and the molecular aspects leading to dysregulated protein synthesis.