Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration

• Published in: Nature reviews. Neuroscience Vol. 13; no. 1; pp. 38 - 50
• Main Authors: Lee, Edward B., Lee, Virginia M.-Y., Trojanowski, John Q.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2012; Nature Publishing Group
• Subjects: 692/420; 692/699/375/365; Alzheimer's disease; Amyotrophic lateral sclerosis; Animal Genetics and Genomics; Animals; Behavioral Sciences; Binding proteins; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development and progression; Disease; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Humans; Laboratories; Medical sciences; Models, Biological; Mutation; Neurobiology; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurology; Neuropathology; Neurosciences; Pathology; Phosphorylation - genetics; Physiological aspects; Protein Processing, Post-Translational - physiology; Proteins; review-article; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Ubiquitination - physiology; Vertebrates: nervous system and sense organs; United States; United States > US; Pennsylvania; Human; Binding protein; Nervous system diseases; Experimental disease; Pathogenesis; Central nervous system disease; Motor neuron disease; DNA binding protein; Degenerative disease; Review; Spinal cord disease
• ISSN: 1471-003X; 1471-0048; 1469-3178
• DOI: 10.1038/nrn3121

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. The involvement of the RNA-binding protein TDP43 in neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration, has become well established. However, the mechanisms by which the protein is linked to the disease process remain unclear. Trojanowski and colleagues describe our current understanding of TDP43 pathology and discuss how gains of toxic function or losses of normal TDP43 function may contribute to neurodegeneration. 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.