NEURONAL DEGENERATION

One paradoxical consequence of the increase of the life expectancy of mankind is the increase of the incidence of those intractable diseases whose risk factor increases with age. The degenerative alterations of the nervous system, associated with such diseases, are at the top of this list. A disease of the motor system, amyotrophic lateral sclerosis (ALS), which currently does not have a cure, deserves special attention compared to the other neurodegenerative disorders. First, since it is relatively easy to design predictive clinical trials in this case, this disease is preferred for drug testing by the pharmaceutical companies compared to the other diseases in which the putative drugs are expected to be distributed in a larger market (e.g. among Alzheimer’s disease patients). A reason for this policy is based on the documented similarity in the majority of destructive processes observed in the degenerative diseases of the nervous system, thus the results can be generalized. Secondly, since the disease also affects the motor axon terminals located in the skeletal muscle, these parts of the nervous system can be sampled without any complications in the patients, and the results of these tests are easily comparable to those obtained from the animal experiments. On the other hand, since neither the cause, nor the exact pathomechanism of the disease is known, explorative basic research is still necessary.

The research of the mechanisms of ALS is built around the anatomy of the voluntary motor system: the pyramidal cells project to the lower motor neurons, which are located in distinct anatomical regions of the brainstem and the ventral horn of the spinal cord. The innervating projections of the lower motor neurons, called peripheral nerves are terminating at the skeletal muscles of the body. During the disease, the progressive destruction of the motor neurons causes the loss of innervation of the muscles and leads to the death of the patients if vital muscles are affected. Although the complete machinery leading to the destruction of the motor neurons is still unknown, some of the details are already disclosed. Such mechanisms are: exhaustion of the motor neurons due to over-excitation, damage of protein and membranous constituents of motor neurons due to the insufficient antioxidant defense, development of deformed cellular structure due to inadequate assembly of the cytoskeleton, immunological and auto-immune reactions, and self- amplifying toxic processes due to the impairment of the calcium homeostasis. According to most recent research data, we are aware that during all these pathological processes not only the motor neurons are involved, but the neighbouring astrocytic and microglial cells also take an active role.

Our recent studies are aimed at unravelling the role of the stability of calcium homeostasis of the motor neurons during degeneration, and to examine if the neighbouring astrocytic and microglial cells could modify their resistance. Methodically, our experiments are based on in vivo, i.e. animal experiments: either production of suitable transgenic animals, or pharmacological treatment or surgery of wild-type and/or transgenic animals would help to answer our specific questions. Detection will be mainly by electron microscopic techniques. This technique, in addition to ultra-structural resolution, could provide information on the composition of the sample under investigation on the micro-analytical scale.

In our light microscopic studies we intend to investigate – in a similar experimental paradigm – the structural and molecular changes in the neighbouring cells. As an example: after characterizing the morphology and distribution of the resting microglial cells in the spinal cord (left panel), motor neurons are experimentally injured and start to express a distress signal (red colour, middle panel), then the change in the microglial population could be determined (middle panel green signal; right panel).