Accumulation of a protein called TDP-43 is an important feature of ALS and frontotemporal dementia. In a newly published research, researchers ‘sow’ this accumulation by fragments of the perpetrator -protein created in the lab. The findings provide further evidence for a prionic paradigm in which proteinaggregation occurs on a template. This breakthrough offers the research field a powerful way to model the mechanisms and to study that stimulate neurodegeneration.
Tar-DNA-Binding Protein 43, better known as TDP-43, is a protein that is found in almost all human cells, where it plays essential roles in regulating gene expression, RNA processing and cellular stress reactions. Under normal circumstances, TDP-43 helps to maintain the health and function of neurons by determining which genes are switched on or switched off and how their messages are translated into proteins.
However, TDP-43 is notorious because of its role in various neurodegenerative diseases, including ALS and frontotemporal dementia, but also Alzheimer’s disease.
From the core for cytoplasm
“TDP-43 pathology is considered a decisive characteristic in almost all as cases and about half of the cases of frontotemporal dementia,” 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 accumulates in one way or another in the cytoplasm where it forms insoluble inclusions and is exhausted from the core.”
Despite its crucial role, the exact processes that stimulate TDP-43 disfunction remain poorly understood-an urgent gap that researchers such as Da Cruz actively work to fill. The destruction and widespread neuronal death follows on following TDP-43-Mis location is probably due to a combination of both disruptions of the normal activities of TDP-43 in the core, as well as the toxic effect of the cytoplasmic inclusions.
“Part of the reason why the underlying mechanisms are still poorly understood is that we miss model systems that reliably summarize both the nuclear exhaustion of TDP-43 and the cytoplasmic aggregation,” says Da Cruz.
Seeds for aggregation
Building on recent reports that autopolidated brain material from patients with TDP-43 inclusions can induce themselves on accumulation of insoluble TDP-43 in cells and transgene mouse models, Da Cruz and its team sowed a way to ‘sow’ this so-called aggregation.
In a study that was recently published in Neuron, the Da Cruz team describes how they produced amyloid-like fibrillen from a fragment of TDP-43 and that these fibrils cause TDP-43 pathology in human cells, including Neurons derived from IPSC.
The inclusions induced by fibril repair many of the most important characteristics that are seen in patients, explains PhD students Rummens: “The TDP-43 aggregates caused by the fibrils that show many of the modifications that we also see in patient brains, including phosphorylasma.”
The similarities extended to other electric effects, because the team identified characteristic gene activity patterns that were previously linked to both aggregation and nuclear loss of TDP-43. The aggregates themselves showed the same heterogeneity in morphology as usually in patients over time.
Tool for research
The new results strongly suggest that pathology in TDP-43 proteinopathies is propagating in a self-representative and prionic way, but many questions remain unanswered. How does TDP-43 get stuck in the aggregates? What do they consist of and how do they cause toxicity? Which extra ‘hits’ are required? What are the effects of TDP-43 mutations? Of age?
So the most important thing is that the new study offers scientists the actual tools to study the various triggers and complex teamwork in a controlled system.
Da Cruz: “We have developed a valuable model that both aspects of TDP-43 pathology display-cytoplasmic aggregation and nuclear exhaustion. This will be a powerful active to help researchers around the world with the unraveling of TDP-43 inducancanisms and can be able to put us in the state.”