Secretion of neurotoxic vesicles by muscle cells of ALS patients

Abstract

To date, amyotrophic lateral sclerosis (ALS) remain incurable and the causes for motor neuron death are unknown. The primary involvement of skeletal muscle in ALS pathogenesis is still controversial. Several studies suggested that a distal axon degeneration occurs prior to the onset of ALS clinical symptoms. Moreover, there are growing evidences for a disruption of exosomes biogenesis and secretion pathways in genetic forms of ALS. Knowing that the skeletal muscle can be a source of exosomes, we hypothesised that ALS skeletal muscle could contribute to the toxic environment of motor neurons and thus participate in ALS pathogenesis through their secretion of exosomes. During my PhD, I investigated the secretion of exosomes by muscle cells from sporadic ALS patients and their role in motor neuron death. First, we show that muscle cells present a consistent signature across ALS patients with an accumulation and over-secretion of exosomes. Second, ALS muscle exosomes are toxic toward healthy human iPSCs motor neurons by inducing shorter, reduced branching neurites and cell death. Third, we observed that ALS muscle exosomes contain FUS protein and are enriched in proteins involved in RNA maturation and transport. Fourth, ALS muscle exosomes induced a disruption in RNA transport in healthy human motor neuron. Fifth, the exosome toxicity is dependent on FUS expression level in the recipient cells, as an over-expression of FUS in the recipient cells exacerbated the ALS exosome toxicity while an inhibition of FUS expression decreased their toxic effect. The greater sensitivity of motor neurons to ALS muscle exosomes might thus be explained by their higher expression level of FUS compare to healthy muscle cells. Altogether, these results suggest that ALS muscle exosomes could contribute to the degeneration of motor neuron in ALS patients.

Date of Award	Sept 2019
Original language	English
Awarding Institution	Sorbonne Université
Sponsors	Sorbonne Université
Supervisor	Stephanie Marie Duguez (Supervisor) & Tony Bjourson (Supervisor)