ROLE OF ALTERED PROTEOLYSIS IN THE DEGENERATION OF MOTOR NEURONS IN in vivo AND in vitro MODELS OF FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS. INVOLVEMENT OF CONSTITUTIVE AND IMMUNO PROTEASOMES AND OF THE AUTOPHAGY-LYSOSOME PATHWAY

Amyotrophic lateral sclerosis (ALS) is a neurological disorder primarily affecting motor neurons, i.e. the neurons responsible for the contraction of muscles that control voluntary movements, speach, swallowing, respiration. The disease, whose causes are still largely unknown, is characterized by a progressive paralysis that leads to death for respiratory failure. As in some familiar forms of ALS there are mutations in the gene that codes for the enzyme superoxide dismutase 1 (SOD1), it has been possible to create experimental models of the disease to facilitate the research on the causes that lead to motor neurons death. Both in ALS patients and in the experimental models the vulnerable neurons contain aggregates of abnormal proteins, whose accumulation can be responsible for the degeneration. It is therefore possible to hypothesize that a role in the pathology is played by dysfunctions of the proteolytic mechanisms, i.e. of the mechanisms that normally degrade intracellular protein. We propose to investigate whether motor neurons degeneration in ALS is due to a failure of protein degradation, using two experimental models (transgenic mice and a motor neuron cell line, both expressing mutant human SOD1) and analyzing two different intracellular proteolytic systems: the proteasomes and the autophagosome-lysosome