Related Experiment Video
Updated: Mar 15, 2026
Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae
Published on: February 25, 2022
In vitro prion-like behaviour of TDP-43 in ALS
Phillip Smethurst1, Jia Newcombe2, Claire Troakes3
1Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
Abstract:
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), and >95% of familial and sporadic cases involve the deposition of insoluble aggregated, phosphorylated and cleaved TDP-43 protein. Accumulating clinical and biological evidence now indicates that ALS bears a number of similarities to the prion diseases, with TDP-43 acting as a misfolded 'prion-like' protein demonstrating similar underlying pathobiology. Here we systematically address the hypothesis that ALS is a prion-like disorder. First we demonstrate that TDP-43 demonstrates seeded polymerisation in vitro directly from both ALS brain and spinal cord. We next show that the seeding of TDP-43 results in the formation of characteristic insoluble, aggregated, and phosphorylated TDP-43 pathology that directly recapitulates the morphological diversity of TDP-43 inclusions detected in ALS patient CNS tissue. We next demonstrate that this reaction can be serially propagated to produce increasing amounts of phosphorylated TDP-43 pathology, and that aggregates can spread from cell to cell in an analogous fashion to that seen in the prion diseases. Finally, we reproduced our findings in a murine motor neuron-like cell line (NSC-34), where the seeding of TDP-43 induces the formation of TDP-43 oligomers and reduced cell viability. These findings may guide therapeutic strategies in this rapidly progressive and invariably fatal disease.
Insights
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease where TDP-43 protein misfolds like a prion. This study shows TDP-43 seeds polymerize and spread, mimicking prion disease mechanisms in ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Disease Research
Background:
- Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by TDP-43 proteinopathy.
- ALS shares similarities with prion diseases, suggesting a common 'prion-like' pathobiology involving TDP-43.
- Over 95% of ALS cases involve insoluble, aggregated, phosphorylated, and cleaved TDP-43.
Purpose of the Study:
- To systematically investigate the hypothesis that ALS is a prion-like disorder.
- To determine if TDP-43 exhibits prion-like properties in the context of ALS.
Main Methods:
- Demonstrated seeded polymerization of TDP-43 in vitro using ALS patient brain and spinal cord tissue.
- Showcased the formation of characteristic TDP-43 pathology recapitulating ALS inclusions.
- Propagated TDP-43 pathology serially and demonstrated cell-to-cell spread.
- Replicated findings in a murine motor neuron-like cell line (NSC-34).
Main Results:
- TDP-43 undergoes seeded polymerization in vitro from ALS tissues.
- Seeded TDP-43 forms insoluble, aggregated, and phosphorylated pathology mirroring ALS inclusions.
- TDP-43 pathology can be serially propagated and spreads between cells, akin to prion diseases.
- TDP-43 seeding in NSC-34 cells induced oligomer formation and reduced cell viability.
Conclusions:
- ALS exhibits prion-like characteristics driven by TDP-43.
- TDP-43 acts as a misfolded protein capable of seeded polymerization and cell-to-cell propagation.
- These findings support ALS as a prion-like disorder and may inform therapeutic strategies.
More Related Videos
06:58Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
Published on: October 18, 2024
13:31Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis
Published on: February 12, 2015
