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NEURODEGENERATIVE DISEASE

TDP-43 shapeshifts to encipher FTD severity

Nature Neuroscience volume 22, pages 3–5 (2019)Cite this article

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TDP-43 forms cytoplasmic aggregates in degenerating neurons of frontotemporal dementia (FTD) patients. Laferrière et al. now establish that TDP-43 assemblies from distinct FTD subtypes have different structures, neurotoxicities, and seeding activities, which correlate with FTD severity. Thus, distinct pathological TDP-43 assemblies akin to prion strains might underpin distinct FTD subtypes.

Amyotrophic lateral sclerosis (ALS) and FTD, a type of frontotemporal lobar degeneration (FTLD), are devastating and fatal neurodegenerative diseases for which there are no effective therapeutics1. A major hallmark of ALS and FTD is the presence of abnormally phosphorylated TDP-43 protein inclusions in the cytoplasm of degenerating neurons1,2. TDP-43 is an intrinsically aggregation-prone, RNA-binding protein with a C-terminal prion-like domain that usually resides inside the nucleus1,2. Thus, the cytoplasmic mislocalization and aggregation of TDP-43 may contribute to disease. Despite this common neuropathology, there exists a large degree of unexplained diversity in the histological and clinical presentations of patients and what appears to be a clinical spectrum of diseases ranging from ALS to FTD1,2. Deciphering the molecular basis for this disease heterogeneity could set the stage for personalized therapeutics aimed at specific disease subtypes.

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Fig. 1: SarkoSpin enables isolation of distinct pathological TDP-43 assemblies from FTLD subtypes that capture disease subtype heterogeneity.

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  1. Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Edward M. Barbieri & James Shorter

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  1. Edward M. Barbieri
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  2. James Shorter
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Correspondence to James Shorter.

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Barbieri, E.M., Shorter, J. TDP-43 shapeshifts to encipher FTD severity. Nat Neurosci 22, 3–5 (2019). https://doi.org/10.1038/s41593-018-0299-6

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