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TDP43 aggregates: the ‘Schrödinger’s cat’ in amyotrophic lateral sclerosis

Nature Reviews Neuroscience volume 22, page 514 (2021)Cite this article

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A recent Review by Tziortzouda et al. (Tziortzouda, P., Van Den Bosch, L. & Hirth, F. Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat. Rev. Neurosci. 22, 197–208 (2021))1 provided a comprehensive overview of TDP43’s physiological functions and described how small dysfunctions in its intrinsic control system might eventually lead to TDP43 pathology. TDP43 protein aggregation is a key element in amyotrophic lateral sclerosis (ALS) as it has a major impact on motor neuron degeneration. However, the statement that all ALS patients present TDP43 abnormalities except for two genetic-related ALS cases is misleading; the only way of determining if TDP43 pathology is there or not is by looking into the ‘sealed box’.

The presence of TDP43 aggregates is not the only culprit of neurodegeneration in ALS, as they are not found in roughly 3–5% of ALS patients and, as mentioned by Tziortzouda and co-authors, TDP43 pathology was not demonstrated in patients carrying FUS mutations. The authors claimed that ALS patients carrying SOD1 mutations also have no TDP43 abnormalities; however, this information is controversial. While several studies have indeed reported an absence of these aggregates, four case reports have demonstrated the occurrence of TDP43 pathology in patients with diverse SOD1 mutations, specifically D91A (ref.2), G86S (ref.3), C111Y (ref.4) and I112T (ref.5) mutations. Furthermore, TDP43 alterations were also shown in mouse models in which Sod1 is mutated and in fibroblasts or hiPSC-derived motor neurons from patients with SOD1 mutations6. In this regard, it is misleading to affirm that TDP43 abnormalities are not found in SOD1-ALS cases.

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  1. UMR1253 iBrain, University of Tours, Tours, France

    Débora Lanznaster, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia & Hélène Blasco

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  1. Débora Lanznaster
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Correspondence to Débora Lanznaster.

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Lanznaster, D., Hergesheimer, R., Vourc’h, P. et al. TDP43 aggregates: the ‘Schrödinger’s cat’ in amyotrophic lateral sclerosis. Nat Rev Neurosci 22, 514 (2021). https://doi.org/10.1038/s41583-021-00477-1

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