The Role of RNA Binding Proteins for Local mRNA Translation: Implications in Neurological Disorders

Abstract

As neurons are one of the most highly polarized cells in our body, they require sophisticated cellular mechanisms to maintain protein homeostasis in their subcellular compartments such as axons and dendrites. When neuronal protein homeostasis is disturbed due to genetic mutations or deletions, this often results in degeneration of neurons leading to devastating outcome such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and fragile X syndrome (FXS). Ribonucleoprotein (RNP) complexes are macromolecular complexes composed of RNA binding proteins (RBPs) and their target RNAs. RBPs contain RNA binding domains and bind to RNA molecules via specific sequence motifs. RNP complexes have various functions in gene expression including messenger RNA (mRNA) trafficking, RNA processing and silencing. In neurons, RBPs deliver specific sets of mRNAs to subcellular compartments such as axons and dendrites to be locally translated. Mutations or deletions in genes coding for RNPs have been reported as causes for neurological disorders such as SMA, ALS, and FXS. As RBPs determine axonal or dendritic mRNA repertoires as well as proteomes by trafficking selective mRNAs and regulating local protein synthesis, they play a crucial role for neuronal function. In this review, we summarize the role of well-known RBPs, SMN, TDP-43, FUS, and FMRP, and review their function for local protein synthesis in neurons. Furthermore, we discuss their pathological contribution to the neurological disorders.

Keywords: ALS; FXS; RNA binding proteins; SMA; local protein synthesis; mRNA translation; neurodegeneration; ribonucleoproteins.

Figure 1

Spinal muscular atrophy (SMA) is caused by mutations or deletions in the SMN1 gene, that lead to reduced SMN protein levels. Physiologically, SMN is mostly found in a complex. Besides snRNP biogenesis and splicing, SMN has important functions such as mRNP granule assembly, axonal mRNA transport and local translation.

Figure 2

Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are caused by multiple mutations leading to defects in RNA metabolism. Mutated TDP-43 or FUS protein aggregates in the cytoplasm and lacks nuclear import. TDP-43 and FUS function physiologically in transcription activation, mRNA splicing, mRNP assembly, axonal transport of mRNA, and local translation. Due to loss of normal protein function and gain of toxic function, RNA metabolism is impaired.

Figure 3

Representation of the protein domain structure of TDP-43 and FUS. The majority of ALS/FTD associated dominant missense mutations in TDP-43 can be found in the glycine-rich c-terminus. Whereas, most ASL/FTLD associated mutations in FUS are described in the nuclear localization signal (NLS).

Figure 4

Fragile X syndrome (FXS) is caused by a trinucleotide repeat expansion in the 5′-UTR of the FMR1 gene. As a result, the RNA binding protein FMRP is lost. FMRP exhibits multiple functions in RNA metabolism as it stabilizes mRNA, transports them along the axon to be locally translated.