Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production

Abstract

Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as essential for a neuron's ability to navigate developmental cues, and to establish, strengthen and remove synaptic connections throughout lifespan. Substantiating the role of RNA processing in the nervous system, several RNA binding proteins have been implicated in both developmental and age dependent neurodegenerative disorders. Of these, TDP-43 is an RNA binding protein that has emerged as a common denominator in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related disorders due to the identification of causative mutations altering its function and its accumulation in cytoplasmic aggregates observed in a significant fraction of ALS/FTD cases, regardless of etiology. TDP-43 is involved in multiple aspects of RNA processing including splicing, transport and translation. Given that one of the early events in disease pathogenesis is mislocalization from the nucleus to the cytoplasm, several studies have focused on elucidating the pathogenic role of TDP-43 in cytoplasmic translation. Here we review recent findings describing TDP-43 translational targets and potential mechanisms of translation dysregulation in TDP-43 proteinopathies across multiple experimental models including cultured cells, flies, mice and patient derived neurons.

Keywords: ALS; FTD; TDP-43; axon; dendrite; neurodegeneration; synapse; translation.

FIGURE 1

Structure and Domain Features of TDP-43. Domain map of TDP-43 depicting the approximate sizes of functional domains. The disease-associated mutations discussed in this review are highlighted. From left to right: N-terminal domain (NTD), nuclear localization signal (NLS), RNA-recognition motif 1 (RRM1), RNA-recognition motif 2 (RRM2), and low complexity domain (LCD). Top left panel: structure of the NTD (PDB ID: 5MDI) with aggregation antagonizing amino acid residues E3, E17, D22, R52, and R55, as indicated (Afroz et al., 2017). The negatively charged NTD residues (red) form salt bridges with positively charged residues (blue) of other TDP-43 NTDs to form oligomers. Top right panel: structure of the tandem RRMs bound to UG-rich RNA (PDB ID: 4BS2) (Lukavsky et al., 2013). The RNA-structure is shown in green with nucleobases represented by blue rectangles.

FIGURE 2

Physiological control of local translation by TDP-43. Post-synaptic translation (top left panel): in dendrites, activation of the post-synaptic neuron triggers the dissolution of dendritic RNP granules that in turn, causes the release of translationally silenced mRNAs making them available for translation. TDP-43 is a component of dendritic RNP granules and regulates dendritic translation of various mRNAs (Rac1, GluR1, Map1b, CamKII) (Wong et al., 2021). Stress and transport granules (bottom panel): TDP-43 associates with stress and RNA transport granules and is necessary for dendritic (Chu et al., 2019) and axonal transport (Alami et al., 2014) of mRNA-containing RNP granules. Axonal translation (top right panel): in axons, TDP-43 regulates local translation of mRNAs for ribosomal proteins (Rp141, Rp126, Rps7) and nuclear encoded mitochondrial proteins (ATP5A1, Cox4i1, Ndufa4) (Nagano et al., 2020; Altman et al., 2021).

FIGURE 3

Translation impairments in TDP-43 proteinopathies. Post-synaptically, TDP-43 proteinopathy prevents the dissolution of dendritic RNP granules (Wong et al., 2021), thereby repressing the local translation of key mediators of synaptic plasticity (Rac1, GluR1, Map1b, CamKII). Cytoplasmic accumulation of TDP-43 in axons results in the formation of RNP condensates and causes a reduction in local translation of various mRNAs, including ribosomal proteins (Rp141, Rp126, Rps7) and nuclear encoded mitochondrial proteins (ATP5A1, Cox4i1, Ndufa4) (Nagano et al., 2020; Altman et al., 2021). TDP-43 proteinopathy reduces axonal mRNA transport as evidenced by a reduction in axonal levels of futsch mRNA at the Drosophila NMJ (Coyne et al., 2015). In Drosophila, TDP-43 proteinopathy represses the translation of dlp, futsch/Map1b, and hsc70-4 causing a reduction in respective protein expression at the NMJ (bottom right panel) (Coyne et al., 2015, 2017; Lehmkuhl et al., 2021). TDP-43 proteinopathy causes Dlp/GPC6 protein to accumulate in puncta at the ventral cord neuropil in Drosophila and ALS spinal cords, respectively (bottom left panel) (Lehmkuhl et al., 2021).