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Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration

Nature Reviews Neuroscience volume 13, pages 38–50 (2012)Cite this article

Subjects

Key Points

  • TAR DNA-binding protein 43 (TDP43) protein is a predominantly nuclear RNA-binding protein that is involved in multiple aspects of RNA processing, including the regulation of pre-mRNA splicing and mRNA stability.

  • TDP43 protein is the major constituent of ubiquitylated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). These inclusions are usually mislocalized within the cytoplasm and are associated with a loss of normal nuclear TDP43 expression. Pathologic TDP43 exhibits a characteristic biochemical profile including ubiquitylation, phosphorylation and cleavage.

  • Ubiquitylation of TDP43 is associated with attempts to degrade TDP43 protein. The identification of disease-associated ubiquilin 2 (UBQLN2) mutations indicates that abnormal protein degradation pathways may lead to TDP43 pathology.

  • TDP43 phosphorylation, cleavage and cytoplasmic localization are all associated with TDP43 aggregation. Data from experimental models suggest that these factors are not absolutely required for TDP43-mediated neurodegeneration.

  • A variety of genetic mutations with diverse functions lead to TDP43 pathology. Dysregulation of TDP43 seems to be a common final pathway that is tightly associated with neurodegeneration.

  • The absence of normal nuclear TDP43 protein in affected neurons is consistent with a loss-of-nuclear-function mechanism of neurodegeneration. Nuclear clearance may be mechanistically linked to the ability of TDP43 protein to autoregulate its cognate RNA.

Abstract

RNA-binding proteins, and in particular TAR DNA-binding protein 43 (TDP43), are central to the pathogenesis of motor neuron diseases and related neurodegenerative disorders. Studies on human tissue have implicated several possible mechanisms of disease and experimental studies are now attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein. In addition, the distinct possibility of pleotropic or combined effects — in which gains of toxic properties and losses of normal TDP43 functions act together — needs to be considered.

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Figure 1: The genetics, pathology and biochemistry of TDP43 proteinopathies.
Figure 2: Normal functions of TDP43.
Figure 3: TDP43 modification, stability and turnover.
Figure 4: Lifecycle of TDP43 pathology.
Figure 5: Subcellular localization of TDP43 protein.
Figure 6: Autoregulation of TDP43 and models of TDP43 toxicity.

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Acknowledgements

We thank our many colleagues working on TDP43 in the Center for Neurodegenerative Disease Research (CNDR) and the Department of Neurology at the University of Pennsylvania for extensive collaborations that provided essential input at many stages of our research on TDP43 since 2006, including L. Kwong who provided immunoblot images. The studies from CNDR that are summarized here were supported by the National Institutes of Health (grants AG10124, AG17586, K08AG039510 and training grant T32 AG00255). V.M.-Y.L. is the John H. Ware III Chair of Alzheimer's Research and J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr, MD Professor of Geriatric Medicine and Gerontology at the University of Pennsylvania. The authors would like to thank the families of their patients who made this research possible.

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  1. Division of Neuropathology, Department of Pathology and Laboratory Medicine, Translational Neuropathology Research Laboratory, University of Pennsylvania, 605B Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Edward B. Lee

  2. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Third Floor Maloney Building, 3600 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Virginia M.-Y. Lee & John Q. Trojanowski

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Glossary

Dominant missense mutation

An alteration of a single nucleotide within a gene, resulting in a codon that encodes for an amino acid that is different from normal. Thus,a change in a single allele is sufficient to result in the mutation-associated phenotype.

Epiphenomena

Secondary processes or events that occur in parallel to a primary event and that may even be a result of the primary event. However, epiphenomena are in addition to the course of a disease and are not necessarily causally related to the primary mechanisms of disease.

High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation

(HITS-CLIP). A method to identify the RNA-binding sites of a given protein in which protein–RNA interactions are stabilized by UV crosslinking. The protein of interest is immunoprecipitated, and the interacting RNA species are identified using high-throughput next-generation sequencing platforms.

RNA granules

Macromolecular structures in neurons enriched with RNA and RNA-binding proteins. They are thought to be involved in the preservation and transport of mRNA

Stress granules

Dense cytosolic protein and RNA aggregations that appear under conditions of cellular stress. The RNA molecules are thought to be stalled translation pre-initiation complexes.

Multivesicular bodies

Endosomal intermediates in which small membrane vesicles are enclosed within a limiting membrane. The internal vesicles are thought to form by invagination and budding from the limiting membrane.

Adaptor protein

A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.

Neuronophagia

The process in which dying neurons are cleared by phagocytic cells including microglia.

Interspecies heterokaryon assays

A test that is performed on cells that contain multiple genetically different nuclei from different species. The test is capable of demonstrating low levels of dynamic nucelo–cytoplasmic shuttling by measuring the transport of a nuclear protein from a donor nucleus to a receptor nucleus.

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Lee, E., Lee, VY. & Trojanowski, J. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13, 38–50 (2012). https://doi.org/10.1038/nrn3121

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