Implications of mRNA translation dysregulation for neurological disorders

Abstract

The translation of information encoded in the DNA into functional proteins is one of the tenets of cellular biology. Cell survival and function depend on the tightly controlled processes of transcription and translation. Growing evidence suggests that dysregulation in mRNA translation plays an important role in the pathogenesis of several neurodevelopmental diseases, such as autism spectrum disorder (ASD) and fragile X syndrome (FXS) as well as neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In this review, we provide an overview of mRNA translation and its modes of regulation that have been implicated in neurological disease.

Keywords: AD; ALS; ASD; FXS; Neurodegeneration; Neurodevelopment; PD; Translational dysregulation; mRNA processing.

Figure 1.. The three steps of cap-dependent mRNA translation.

A- The first step of translation is the initiation. It is also the most tightly regulated step and involves the assembling of the ternary complex (TC) containing the tRNA and eIF2. The TC then associates with eIF1, eIF1A, eIF3, eIF5 and 40s subunit to form the pre-initiation complex (PIC). The open PIC binds to the 5’ end of the mRNA. PIC then scans the mRNA until it recognizes a start codon. Release of eIF1, eIF2 and eIF5, and recruitment of 60S subunit mark the formation of the 80S initiation complex (IC). B- The second step of translation is the elongation. It involves the repetition of the process of adding amino acids to a growing polypeptide chain. The translational machinery moves along the mRNA so each codon cycles through the processes of preparation for binding (A site), binding (P site), and release (E site) until it reaches the stop codon and the whole peptide chain is synthesized. C- The third and final step is the termination. This step begins when eRF1 recognizes the stop codon and consequently arrests translation. This phase culminates with the disassembly of the ribosome-mRNA complex and release of the completed polypeptide chain.

Figure 2.. Modes of dysregulation of mRNA translation associated to neurological diseases.

Representation of the different types of mRNA translation dysregulation and examples of how they affect neuronal function and the mechanisms by which they associate to neurodevelopmental and neurodegenerative diseases. Autism Spectrum Disorder (ASD) and autistic behavior have been associated to loss of 4EBP2 and overexpression of eIF4E. Mutations in genes that participate in translation have also been associated to ASD such as FMRP, eIF4E, TSC1, TSC2, and PTEN. Fragile X Syndrome (FXS) is caused by CGG expansion within the gene which encode for FMRP. Reduction or loss of FMRP expression increases translation and dendritic spines. Alzheimer’s Disease (AD) pathophysiology may involve association of tau and ribosomes as well as increase of phosphorylated eIF2α which lead to increase in mRNA translation. On the other hand, neuronal exposure to amyloid beta (Aβ) increases FMRP-regulated protein synthesis by reducing overall CYFIP2 levels. Parkinson’s Disease (PD) patients’ brains have shown altered levels of eIF3, eIF1, eEF1A, and eEF2 in different stages of the disease. It is also known that LRRK2 can phosphorylate 4EBP1 and regulate miRNA regulating translation. Amyotrophic Lateral Sclerosis (ALS) disease causing mutations in genes encoding for SOD1, TARDBP, FUS, and C9orf72 are known to be involved in mRNA metabolism. TDP-43 can also associate with FMRP and suppress translation. Additionally, stress granules can contain mRNAs, eIFs and RBPs which are all known to regulate translation.