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Maladies des MotoNeurones : Modélisation et Thérapie

In the aging populations of Western countries one out of four persons is at risk for a neurodegenerative disease. Among neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) is a particularly devastating and always fatal disorder which does not benefit from effective therapies. ALS affects motor neurons in cerebral cortex, brainstem and spinal cord leading to progressive muscle atrophy and paralysis. While most forms of ALS appear sporadically, about 10-20 % are familial and caused by mutations in genes encoding proteins as diverse as superoxide dismutase 1/SOD1 (ALS1), Alsin (ALS2), VAP-B (ALS8), TDP-43, FUS/TLS, CHMP2B or Optineurin. While the molecular mechanisms of ALS remain controversial, a consensus emerges on its natural disease history. According to studies in mutant SOD1 mice, motor neuron degeneration first manifests far distally at the neuromuscular synapse with loss of synaptic vesicles and axon retraction but is initiated in the cell body and modulated by neighboring astrocytes and microglia. Our team hypothesizes that the Golgi apparatus may link peripheral manifestation, central initiation and neuron/glia-interactions in ALS. This novel and potentially unifying hypothesis is corroborated by the following observations :

  • The Golgi apparatus plays a key role in protein secretion to the extracellular space, vesicle routing to the neuromuscular synapse and is increasingly recognized as a sensor and transducer of cell death signals.
  • Ultrastructural, molecular and functional Golgi abnormalities have been observed in motor neurons from human patients with various forms of ALS and corresponding mouse models.
  • An increasing number of ALS genes encode proteins normally involved in the function of the Golgi apparatus and related organelles. In order to test the hypothesis, the team pursues the following specific aims :
  • To investigate how mutations in ALS genes trigger Golgi pathology, endosome dysfunction and synaptic vesicle loss in motor neurons.
  • To dissect out the mechanisms converging from Golgi dysfunction to cell death and axon degeneration.
  • To identify such pathological changes in motor neurons from human ALS patients.
  • To use this knowledge for the development of new experimental therapies.

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