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Unraveling the contribution of local translation to NMJ degeneration in FUS-ALS
Amyotrophic lateral sclerosis (ALS) is a devastating disease which is characterized by the loss of motor neurons of the motor cortex and spinal cord. Most of the ALS cases are unpredictable, but several genetic causes have been found in the population accounting for mutations in genes encoding SOD1, TDP-43, FUS and C9ORF72 proteins. All the different ALS forms have in common denervation of the neuromuscular junctions (NMJs), the contacts between the axons and the muscle, which are critical for our most basic functions including breathing and walking. The mechanisms through which this structure is non-functional and eventually lost during disease are currently unknown. Recently, we demonstrated that in animals modeling inherited forms of disease the production of proteins along the axons, called axonal local translation, is impaired and this correlates with aberrant composition of the axonal and synaptic translation machinery and ribosomes, all of which are responsible for protein production. This project will unveil the local translation events in a healthy NMJ and will investigate at the same time the contribution of aberrant local translation to NMJ demise driven by ALS-causing mutations in FUS and other forms of ALS. This work ultimately will uncover the local mechanisms leading to disease pathogenesis for the identification of synaptic targets whose translation can be modulated to rescue disease phenotypes, with the promise to translate these findings to the clinic.
Grantee: Diana Piol, Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Vlaams Instituut voor Biotechnologie (Flanders Institute for Biotechnology, VIB)
Country: Belgium