Eva Hedlund

Motor neurons (MNs) and skeletal muscle fibers need to maintain bidirectional communication to avoid synaptic breakdown and systemic failure of motor control. However, we do not understand what meditors regulate their communication. In addition to communication over their synapse, the neuromuscular junction (NMJ), MN and muscle are thought to rely on autocrine, paracrine and endocrine signals, which are largely unknown. In the lethal disease ALS, the NMJ is the first pathological target with subsequent axonal degeneration, followed by muscle atrophy and paralysis. Recent evidence strongly suggests that there is systemic dysregulation of energy metabolism in ALS and that multiple cell types may contribute early on to MN pathology, but the underlying molecular mechanisms are unknown. As MNs have high energy demand, impairments in energy metabolism of multiple cell types that MNs rely upon could explain their selective degeneration in ALS. Our hypothesis is that in ALS, dysregulation of energy metabolism of multiple cell types synergistically provoke disturbances in cell-cell communication, causing disruption of the NMJ with subsequent MN degeneration. We will investigate how human MNs, muscle, oligodendrocytes, astrocytes and fuel-supplying tissues communicate to support neuromuscular function and how disease-related disruption in bioenergetic leads to subsequent miscommunication between multiple cell types promoting collapse of the NMJ and consequently leading to ALS.