Frank Hirth and his team, King’s College of London is the recepient of a grant for a project started in 2011 whose objective is to understand the mechanisms leading to the accumulation of the protein TDP43.

The first results have just been published in two peer rewees scientific journals : Human Molecular Genetics  et  Cell Reports

A new important axis of research currently focuses on the accumulation of intracellular abnormal proteins found in ALS. The phenomenon of accumulation is described in other very common neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s but also very rare as the disease of Creutzfeldt Jakob (prion diseases). The proteins become abnormal because they change conformation, they go to aggregate or even spread (a phenomenon described the prion proteins) and become toxic to the cell

Project : Genetic dissection of TDP-43 signaling in a Drosophila model of ALS

Recently it was shown that abnormal aggregates found in affected nerve cells of ALS patients are enriched with TDP-43 protein (Tar DNA binding protein of 43 kDa), and that several familial as well as sporadic ALS patients have a mutation in the coding gene. These findings strongly suggest that dysfunction of TDP-43 is causally related to ALS formation. However, the underlying mechanisms are not understood.

The fruitfly Drosophila is an ideal model system to study ALS. Although the fly has a less complex central nervous system than humans, the major building blocks are comparable, especially motor neurons and muscle innervation. Drosophila encodes a TDP-43 protein that is similar to the human protein affected in ALS.

Human Molecular Genetics : Diaper et al

Diaper et al identified for the first time early events causing disease formation seen in ALS. They used the fruitfly Drosophila as an animal model to study the role of TDP-43 which has been identified as the major disease protein in ALS. The new findings demonstrate that both loss and gain of TDP-43 function can trigger disease formation. Moreover, for the first time, the findings by Diaper, Adachi and colleagues identify functional deficits at connections between nerve cells, so called synapses, as an initiating event underlying disease formation. These deficits result in defective communication between nerve cells which in turn leads to movement abnormalities and the progressive deconstruction of neuronal connections, ultimately causing the age-related loss of nerve cells which characterizes ALS. This study may thus help identifying clinical strategies and therapeutic interventions for the treatment of ALS.

Cell Reports: Vanden Broeck et al.

Vanden Broeck et al identified for the first time a process how ALS may form. They also used the fruitfly Drosophila as an animal model to study the causes underlying ALS formation. Similar to the disease condition, Vanden Broeck and colleagues generated flies which either produce too much or not enough of TDP-43, the major disease protein in ALS. They found that in both cases, the flies did not develop properly and showed signs of neurodegeneration caused by defective steroid receptor signalling, a process whereby hormones regulate the maturation and survival of nerve cells. Since defective hormone signalling has been implicated in motor neuron diseases, the study by Vanden Broeck et al identifies a disease pathway leading to ALS which can be targeted for therapeutic treatment of the disease.