Beyond the neuromuscular junction: dysfunction of spinal synaptic targets of motoneurons in Amyotrophic Lateral Sclerosis

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Every year more than 5000 people are diagnosed with Amyotrophic Lateral Sclerosis (ALS). Its outcome is always fatal, with a median survival time from diagnosis of only 4-5 years. The initial symptoms include muscle weakness, cramps, and twitching. ALS is a disease of the central nervous system that mostly targets motoneurons. Motoneurons are located in the spinal cord and send their long processes throughout the body making contacts with distinct muscle groups. Through these contacts motoneuron activation leads to muscle contraction and to execution of all motor tasks, from walking to grasping, chewing, and even breathing. During the early symptomatic stages of the disease, contacts made by motoneurons onto muscles become ineffective, hampering successful execution of motor tasks. This is followed by progressive motoneuron death, leading to more severe motor deficits, inability to walk, bear weight, or handle objects. The degeneration progresses along the spinal cord and extends to motoneurons responsible for the contraction of the diaphragm necessary for respiration. This is normally the final stage of the disease, in which the patient maintains full awareness, but becomes progressively incapable of unassisted breathing.Currently there is no cure and the only approved treatments (such as riluzole, a compound that reduces the excitability of motoneurons) only marginally prolong the life expectancy. The causes of the disease are unknown, but in at least 20% of patients there is a family history that proves a hereditary trait. Indeed, familial studies led to the identification of several mutations in proteins that affect the health of motoneurons. A major breakthrough resulted from this knowledge: these mutations were used to develop animal models of the disease.We are proposing to use two of these animal models that are quite different from each other, but whose symptoms closely mirror the symptoms and time course of ALS in the corresponding affected human patients. Previous research has focussed on the analysis of cellular events in motoneurons that could lead to degeneration and death. While a number of key events have been identified, the cause-effect relationships proved hard to pinpoint, thus making it difficult to develop therapeutic strategies.In our proposal we hypothesize that motoneuron degeneration is not only due to events occurring at the molecular level within single cells, but also due to events within circuits regulating motor control. In particular, we will focus on local circuits between motoneurons and a special class of inhibitory neurons called Renshaw cells that have the role of limiting and fine tuning the excitation of motoneurons. Disruption of these circuits may cause a vicious cycle in which motoneurons become over excitable and degenerate as a consequence of the excessive, unchecked amount of excitation they receive. There is some previous evidence of disruption of this circuit in both affected humans and mutated animals, and our research will quantify the extent and time course of this disruption. Our investigation has a dual purpose: first, by understanding how and when the local circuits are affected, we may be able to devise a diagnostic test that could reveal early stages of the disease, well before clear symptoms appear. This would potentially open a longer therapeutic time window. Second, the demonstration of the importance of the disruption of local circuits in the development of the disease could open the way to the development of new therapies aimed at preserving and enhancing normal local circuit function.