Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism.

Abstract

The human TAR DNA binding protein 43 (TDP-43), encoded by the gene TARDBP, plays a central role in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP-43 inclusions are also found in up to approximately 60% of Alzheimer's disease (AD) brains. Although ALS-causing TARDBP mutations cluster in the C-terminal glycine-rich region of the protein, the pathogenic nature of the atypical missense variants p.A90V (located between the bipartite nuclear localization signal) and p.D169G (located in the first RNA-binding domain) is unclear. In addition, whether causal ALS mutations represent gain or loss-of-function alleles remains unknown. We recently reported that loss-of-function of the highly conserved TARDBP ortholog in Drosophila (called TBPH) leads to death of bursicon neurons resulting in adult maturation and wing expansion defects. Here, we compared wild-type TARDBP, 2 typical ALS-causing mutations (p.G287S and p.A315T) and 2 atypical variants (p.A90V and p.D169G), for their ability to complement neuronal TBPH loss-of-function. Although p.D169G rescued organismal pupal lethality and neuronal loss to a similar extent as wild-type TARDBP, p.A90V, p.G287S, and p.A315T were less efficient. Accordingly, p.A90V, p.G287S, and p.A315T but not p.D169G or wild-type protein promoted a shift of TDP-43 from the nucleus to the cytoplasm in approximately 12%-14% of bursicon neurons. Finally, we found that the carrier frequency of rare variant p.A90V was higher in French-Belgian AD cases (5/1714, 0.29%) than in controls of European descent (5/9436, 0.05%) (odds ratio = 5.5; 95% confidence interval, 1.6-19.0; p = 0.009). We propose that pathogenic TARDBP mutations have partial loss-of-function properties and that TARDBP p.A90V may increase AD risk by the same mechanism.

• Authors: Lies Vanden Broeck, Gernot Kleinberger, Julien Chapuis, Marc Gistelinck, Philippe Amouyel, Christine Van Broeckhoven, Jean-Charles Lambert, Patrick Callaerts, Bart Dermaut
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 36 Issue 2 Pg. 1121-9 (Feb 2015) ISSN: 1558-1497 [Electronic] United States
• PMID: 25442115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human

Topics

• Alleles
• Alzheimer Disease (genetics)
• Amyotrophic Lateral Sclerosis (genetics)
• Animals
• DNA-Binding Proteins (genetics, physiology)
• Drosophila (genetics)
• Female
• Forecasting
• Frontotemporal Dementia (genetics)
• Genetic Variation (genetics)
• Humans
• Male
• Mutation
• Neurons (pathology)