FUNCTIONALE ROLE OF ALSIN IN ENDOCYTIC TRANSPORT AND SIGNAL TRANSDUCTION AND IMPLICATIONS FOR AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a disease that belongs to a class of disorders affecting the part of the nervous system that controls muscles. Some symptoms are treatable, but ALS is a progressive, fatal disease. It occurs when motor neurons, specific cells in the brain and in the spinal cord, gradually degenerate. When these cells die, the brain cannot signal voluntary muscle control. Because of the absence of the stimulus, the muscle tissues under the control of the affected neurons weaken and waste away, leading to paralysis of the patients. In most of the cases the disease is sporadic. In approximately 10% of cases, ALS is a familial disease caused by mutations in three different genes. One encode for a protein named Alsin. Its function is not known, but Rab5 is probably its substrate. Rab5 is a key regulator of endocytosis, a process essential for normal cell physiology. Up to date, it is unclear what goes wrong in cells when Alsin is mutated. I therefore want to investigate in how far processes normally controlled by Rab5 are compromised by Alsin mutations, and in how far disturbance of such processes contribute to the problems ALS patients are suffering from. Such knowledge could lay the basis for therapeutical treatment of Alsin-related ALS cases.In order to identify such processes, I will determine where exactly in healthy cells the Alsin protein resides. As we have a good idea in which regions of the cell various processes occur, this study can provide ideas as to the processes Alsin participates in. For many cellular processes involving Rab5 we have well established experimental systems, and hence I should be able to subsequently experimentally determine the role of Alsin in such distinct process. Finally, I plan to validate my obtained data by genetically manipulating an animal model, probably the mouse, which should lead to a phenotype resembling the human ALS pathology.