TDP-43 enhances translation of specific mRNAs linked to neurodegenerative disease

Abstract

The RNA-binding protein TDP-43 is heavily implicated in neurodegenerative disease. Numerous patient mutations in TARDBP, the gene encoding TDP-43, combined with data from animal and cell-based models, imply that altered RNA regulation by TDP-43 causes Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. However, underlying mechanisms remain unresolved. Increased cytoplasmic TDP-43 levels in diseased neurons suggest a possible role in this cellular compartment. Here, we examined the impact on translation of overexpressing human TDP-43 and the TDP-43A315T patient mutant protein in motor neuron-like cells and primary cultures of cortical neurons. In motor-neuron like cells, TDP-43 associates with ribosomes without significantly affecting global translation. However, ribosome profiling and additional assays revealed enhanced translation and direct binding of Camta1, Mig12, and Dennd4a mRNAs. Overexpressing either wild-type TDP-43 or TDP-43A315T stimulated translation of Camta1 and Mig12 mRNAs via their 5′UTRs and increased CAMTA1 and MIG12 protein levels. In contrast, translational enhancement of Dennd4a mRNA required a specific 3′UTR region and was specifically observed with the TDP-43A315T patient mutant allele. Our data reveal that TDP-43 can function as an mRNA-specific translational enhancer. Moreover, since CAMTA1 and DENND4A are linked to neurodegeneration, they suggest that this function could contribute to disease.

Global cataloguing of variations in untranslated regions of viral genome and prediction of key host RNA binding protein-microRNA interactions modulating genome stability in SARS-CoV-2

“…For the first time, we report the likelihood of TARDBP binding to this region. TARDBP has been known to promote translation and RNA stability and it has also been shown to play important role in viral infection [42,43]. Therefore, promotion of translation of SARS-CoV-2 viral proteins by TARDBP fits well with possible selection of 'T' base over time and its correlation to infectivity.…”

Cytoplasmic functions of TDP-43 and FUS and their role in ALS

“…Moreover, in fractionation studies, TDP-43 and FUS co-migrate with both actively translating polyribosomal fractions as well as non-translating RNP fractions comprising monosomes, ribosomal subunits and RNP complexes [36,40]. This suggests that dependent Dennd4a regulation is only mediated by mutant TDP-43, which binds the 3' UTR region of the transcript and promotes its translation [44]. Enhanced translation in a mutant TDP-43 mouse model (A315T) has also been reported for Ccl4 and Ddx58, however it is unclear whether this is due to differential transcript expression or increased synthesis [45].…”

Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

“…HD symptoms appear after birth, and the severity depends on the number of CAG repeats in HTT. Brain pathology and MRI studies show early damage to the striatum and cortex, and as the disease progresses, it affects multiple CNS and peripheral regions, leading to motor dysfunctions, weight loss, and energy deficits (20)(21)(22). These deficits in HD can emanate from one or more of the effects of mHtt on functions, such as vesicle-and microtubule-associated protein/organelle transport, transcription, autophagy as well as tissue maintenance, secretory pathways, and cell division (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

“…These deficits in HD can emanate from one or more of the effects of mHtt on functions, such as vesicle-and microtubule-associated protein/organelle transport, transcription, autophagy as well as tissue maintenance, secretory pathways, and cell division (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). mRNA translation is crucial for cell growth and survival, and increasing data indicates that its dysregulations contributes to neurodegenerative disorders (22,23). We previously identified mHtt as a potentiator of amino acid-induced mTORC1 signaling in association with Rheb and found that the selective upregulation of mTORC1 in the striatum worsened HD behavioral defects (24).…”