Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SS, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, Clare AJ, Badders NM, Bilican B, Chaum E, Chandran S, Shaw CE, Eggan KC, Maniatis T, Taylor JP. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron. 2014 Feb 5;81(3):536-43. PubMed.
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University of Trieste
The pathogenetic mechanisms whereby TDP-43 alterations lead to ALS and FTLD are far from being clear. Defining these processes is challenging since TDP-43 is a "multitasking" protein, implicated in different aspects of RNA metabolism.
Thus, before evaluating possible therapies targeting TDP-43, most researchers' efforts are still devoted to characterizing TDP-43's pathophysiological functions.
Earlier observations by other groups suggested that neuromuscular junction alteration was one of the possible consequences of the lack of functional TDP-43. However, there was only indirect evidence for putative axonal spreading of TDP-43.
In this context, the work now published by the group coordinated by Dr. Taylor further addressed this issue in three different models: in vivo in Drosophila, in mouse cortical neurons, and in human stem cell-derived motor neurons from ALS patients.
The authors were able to demonstrate that TDP-43 is implicated in the anterograde axonal transport of specific mRNAs from the soma to distal axonal compartments, including the neuromuscular junctions.
Till now, TDP-43 functions have been mostly limited to the nucleus, with some incursions in the cytoplasm through shuttling processes.
This work now lends support to a novel "cytoplasmic" role for this nuclear factor, specifically related to the axonal transport.
The importance of this new function for TDP-43 goes along with the observation that this activity seems to be conserved through evolution (not only in the "next of kin" mouse but also in the "distantly related" fruit fly). This is consistent with the previously characterized splicing-related functions of the human and Drosophila TDP-43 orthologs.
In addition, it is intriguing that two TDP-43 mutations (M337V and A315T) seem to alter the TDP-43 "cargo" function. In this respect, it should be noted that previous works have shown that these amino acid changes cause neurotoxicity in different animal models (including Drosophila) without a clear demonstration that they alter the splicing-related function of TDP-43, or its ability to interact with other proteins or to form aggregates.
However, it should be kept in mind that the number of patients affected by ALS (and other neurodegenerative diseases) who carry TDP-43 mutations is limited and that age of onset of the disease in patients is extremely variable, suggesting that other endogenous and exogenous factors might contribute to prime/modulate TDP-43 proteinopathies and trigger the onset of neurodegenerative disorders.
Nevertheless, the involvement of TDP-43 in axonal protein transport is an important milestone in our knowledge of its functions. In the future it will be important to understand the "mission" of this transport and identify additional factors involved, as well as the targets of this transport.
Overall, Dr. Taylor's group has carried out a very insightful piece of work that will allow us to shed further light on the puzzling pathogenesis of ALS and other TDP-43 related diseases.
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