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Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation

French, RL; Grese, ZR; Aligireddy, H; Dhavale, DD; Reeb, AN; Kedia, N; Kotzbauer, PT; ... Ayala, YM; + view all (2019) Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation. Journal of Biological Chemistry , 294 (17) pp. 6696-6709. 10.1074/jbc.RA118.005889. Green open access

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Abstract

Aggregates of the RNA-binding protein TDP-43 (TAR DNAbinding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stage is primarily driven by TDP-43’s RNA-binding region. Specific binding to GU-rich RNA strongly inhibited both TDP-43 oligomerization and aggregation, suggesting that RNA interactions are critical for maintaining TDP-43 solubility. Moreover, we analyzed TDP-43 liquid–liquid phase separation and detected similar detergentresistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that aggregates generated from purified TDP-43 seed intracellular aggregation detected by established TDP-43 pathology markers. Remarkably, cytoplasmic aggregate seeding was detected earlier for the A315T and M337V variants and was 50% more widespread than forWTTDP-43 aggregates.We provide evidence for aninitial step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbationsin TDP-43 homeostasisin protein aggregation and ALS-FTD pathogenesis.

Type: Article
Title: Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.RA118.005889
Publisher version: https://doi.org/10.1074/jbc.RA118.005889
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ALS mutation, RNA binding protein, TAR DNA-binding protein 43 (TDP-43) (TARDBP), amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease), frontotemporal dementia (FTD), liquid droplet, liquid–liquid phase separation, neurodegeneration, protein aggregation, ribonuclear protein (RNP)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10077762
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