Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations

By Nael H. Alami, Rebecca B. Smith, M. Carrasco, Luis A. Williams, C. Winborn, Steve S. W. Han, E. Kiskinis, Brett J. Winborn, Brian D. Freibaum, A. Kanagaraj and 9 more. Neuron, 2014

648 citations recorded by the source corpus.

Summary The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

Subfields: Cellular and Molecular Neuroscience, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/fe8b9639493456bc958c31f63ea95cf6c75be0bd

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Citations in the corpus

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function (2015, background): “…could arise through several molecular mechanisms that are not mutually exclusive, including: altering intracellular transport of FUS granules (Alami et al., 2014; Liu-Yesucevitz et al., 2014), and, as we have shown here, trapping cargo proteins (e.g., TIAR-1) involved in regulating local RNA…”
ALS mutations disrupt phase separation mediated by -helical structure in the TDP-43 low complexity C-terminal domain (2016, background): “…in the TDP-43 C-terminal domain are critical for LLPS. ALS-associated mutations disrupt interactions and inhibit LLPS, suggesting a molecular mechanism for the observed loss of function (Arnold et al., 2013) and alteration in granule assembly (Alami et al., 2014) linked to these same variants.”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “In fact, ALS-associated TDP-43 mutants were found to impair the transportation of the RNP granules (Wang et al., 2008; Alami et al., 2014). mRNA Translation Proteomics has revealed the TDP-43’s global protein interaction profile which has also identified several partner proteins involved in the RNA…”
Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules (2018, result): “The RBPs found in neurite-localized SGs were enriched in functions such as RNA transport and translational suppression (Figure S4C), which is consistent with and extends previous studies reporting that axonal transport is impaired in ALS motor neurons (Alami et al., 2014; Yasuda and Mili, 2016).”
AXONAL TRANSPORT: CARGO-SPECIFIC MECHANISMS OF MOTILITY AND REGULATION (2014, background): “These RNA granules exhibit bidirectional as well as confined oscillatory movement dependent on plus- and minus-end-directed microtubule-based motors (Alami et al., 2014; Davidovic et al., 2007; Gumy et al., 2014; Kanai et al., 2004; Ling et al., 2004; Zhang et al., 2001).”