New Model Mimics TDP-43 Aggregation in ALS and Frontotemporal Dementia
A new lab model replicates TDP-43 aggregation in ALS and frontotemporal dementia, aiding research into disease mechanisms.
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A team of researchers has developed a laboratory model that recapitulates the pathological aggregation of TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The findings, published in Neuron, demonstrate that fragments of TDP-43 can seed its aggregation in human cells, including induced pluripotent stem cell (iPSC)-derived neurons.
TDP-43 (TAR DNA-binding protein 43)
A protein involved in gene expression and RNA processing. It plays a key role in maintaining neuron function but is known for forming toxic aggregates in neurodegenerative diseases.iPSC (induced pluripotent stem cell)
A type of stem cell generated by reprogramming adult cells. iPSCs can differentiate into various cell types, including neurons, and are widely used in disease modeling.TDP-43 is a protein found in nearly all human cells. It plays an essential role in regulating gene expression and RNA processing, and in mediating responses to cellular stress. In neurons, it contributes to cell health by controlling how genetic information is translated into proteins.
Pathological changes in TDP-43, including its accumulation and mislocalisation, are linked to several neurodegenerative disorders. These include ALS and frontotemporal dementia, as well as some cases of Alzheimer’s disease.
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Subscribe for FREECytoplasmic accumulation and nuclear loss
In healthy cells, TDP-43 is predominantly located in the nucleus. In the brains of individuals with ALS and frontotemporal dementia, however, it accumulates in the cytoplasm and forms insoluble aggregates. This mislocalisation is accompanied by a depletion of TDP-43 from the nucleus.
“TDP-43 pathology is considered a defining feature in nearly all ALS cases and about half of frontotemporal dementia cases,” explains professor Sandrine Da Cruz, group leader at the VIB-KU Leuven Center for Brain & Disease Research. “In the brains of these patients, TDP-43 somehow mislocalizes, accumulates in the cytoplasm where it forms insoluble inclusions, and is depleted from the nucleus.”
The mechanisms underlying this shift remain unclear. While cytoplasmic inclusions are thought to be toxic, the loss of TDP-43 from the nucleus may also contribute to disease progression by interfering with its normal functions.
Progress in understanding these mechanisms has been hampered by the lack of robust model systems that replicate both nuclear depletion and cytoplasmic aggregation.
Seeding aggregation with synthetic fibrils
Building on earlier observations from postmortem brain tissue, researchers generated amyloid-like fibrils from a fragment of TDP-43 in vitro. When introduced into human cells, these fibrils induced TDP-43 pathology, including cytoplasmic aggregation and nuclear loss.
Amyloid-like fibrils
Protein structures that form from misfolded proteins. They are associated with a range of neurodegenerative diseases and can induce further misfolding in nearby proteins.Phosphorylation
A biochemical process that modifies proteins and can influence their function or location. In neurodegenerative diseases, abnormal phosphorylation can lead to protein dysfunction.Ubiquitination
A cellular process where proteins are tagged for degradation. Dysregulation of this process can result in the accumulation of damaged or misfolded proteins.In the study, fibril-induced aggregates shared key features with those observed in patient tissue. These included post-translational modifications such as phosphorylation and ubiquitination. Notably, the fibrils prompted the recruitment of native TDP-43 from the nucleus to the cytoplasm.
The researchers also found that cells with TDP-43 aggregates exhibited gene expression changes similar to those previously associated with protein mislocalisation. The aggregates themselves displayed morphological variability, a feature often seen in patient samples over time.
A controlled system to study TDP-43 pathology
The results support a prion-like model in which TDP-43 aggregation spreads through templated misfolding. However, many questions remain unresolved, including the composition of the aggregates, the pathways leading to toxicity and the potential role of TDP-43 mutations or ageing.
The new model provides researchers with a tool to explore these questions in a controlled environment. By mimicking both major pathological features of TDP-43 proteinopathies, the system offers a platform for further investigation of disease mechanisms and for the screening of experimental therapeutics.
Reference: Rummens J, Khalil B, Yıldırım G, et al. TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43. Neuron. doi: 10.1016/j.neuron.2025.03.004
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