TDP-43: A key protein in ALS and FTD
Neuropathologists have known for decades that there are similar protein deposits in the nerve cells of patients with amyotrophic lateral sclerosis (ALS) and many patients with frontotemporal dementia (FTD). However, for a long time it was not possible to determine exactly what they consist of. Around 2006, scientists were able to prove beyond doubt that it is the protein TDP-43 (Manuela Neumann et al. Science 2006). The parallel between the two neurodegenerative diseases is striking: in ALS, deposits of TDP-43 occur in around 95 percent of patients, in frontotemporal dementia in 50 to 60 percent of those affected. This form is now referred to as FTLD-TDP.
Although the deposits form at different locations in the brain in both diseases, the effects are similar: the characteristic accumulation of the TDP-43 protein marks the beginning of the development of far-reaching neuronal changes with serious consequences. Because the processes that lead to damage and loss of nerve cells are similar in both diseases, it is suspected that TDP-43 plays a key role in the development of these diseases.
TDP-43 is the abbreviation for Transactive Response DNA Binding Protein 43kDa. Normally, the protein regulates important cellular processes, predominantly in the nucleus of a cell. However, if the protein misfolds and aggregates, it is deposited in the cell body - and this is exactly what happens in patients with ALS and FTLD-TDP. In addition, many Alzheimer's patients also experience focal TDP-43 deposition, which can presumably further impair brain function.
How TDP-43 deposition disrupts central nervous system function
In ALS, TDP-43 deposits are directly linked to the muscle weakness characterizing the disease. All muscles in the human body are controlled by so-called motor neurons. The upper motor neurons are located in a small area in the cerebral cortex (precentral) and control the lower motor neurons in the spinal cord, which ultimately trigger the contraction of individual muscle fibers. In healthy people, they work together smoothly. However, it is precisely in these motor neurons that TDP-43 is deposited. The interaction no longer works, resulting in paralysis, spasticity and increased reflexes - i.e. the various muscle dysfunctions that occur in ALS. Ultimately, the motor neurons die off completely, which explains the progressive muscle weakness and paralysis in ALS patients.
In FTLD-TDP, TDP-43 deposits are found particularly in the frontal and temporal cerebral cortex. These regions are responsible for a person's behavior, personality, emotions, planning and language. As the disease progresses, the nerve cells in these regions lose their function and eventually die. This leads to the typical clinical symptoms of FTD with socially inappropriate behavior, impulsive or thoughtless actions, apathy and loss of empathy with relatively little impairment of memory.
The fatal effects of protein accumulation
There are two main problems with TDP-43 in ALS and FTLD-TDP. The first is loss of function. Normally, TDP-43 in the cell nucleus is involved, among other things, in ensuring that the RNA in the cell nucleus is properly assembled so that correct proteins are formed. TDP-43 plays a role in thousands of RNAs.
Another function has recently come into focus: TDP-43 keeps RNA sequences under control that should not be converted into proteins. When TDP-43 fails, it causes what is known as “cryptic exons”. This means that the cells suddenly read the wrong sections of RNA and produce defective proteins as a result. You could imagine this as if a book had faulty, randomly inserted pages that make the text incomprehensible. This error in RNA processing leads to serious disturbances in the cells.
The second problem is aggregate toxicity. TDP-43 begins to accumulate outside the cell nucleus and clumps together to form so-called aggregates. These protein deposits are toxic and disrupt vital cell functions. It is as if a cell's workplace becomes so cluttered with useless material that nothing can work properly anymore. The cell loses its ability to repair itself, remove waste and process important signals. The nerve cells controlling movement therefore die.
Therapeutic approaches on the horizon
For the treatment of ALS and FTLD-TDP, researchers want to remedy the loss of function, among other things. For example, it has been shown that stathmin-2, an important protein in motor neurons, is impaired by TDP-43 deposits. A procedure is currently undergoing clinical trials that aim to correct the impaired production of stathmin-2, possibly slowing down the disease. This involves the use of so-called antisense oligonucleotides, a genetic engineering tool.
Other approaches are aimed at directly hindering the deposition of TDP-43 or dissolving the deposits. This could be achieved through immunotherapies in which antibodies are produced against “sick” TDP-43 in order to achieve the degradation of these deposits.