Energizing and Protecting Axons Through Metabolic Coupling to Schwann Cells

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Axons and their associated glia (Schwann cells and oligodendrocytes) form the largest part of the neuronal network. Axons are challening to maintain energetically and are vulnerable to a wide spectrum of noxious stimuli. Dysfunction of axons and pathological axon degeneration (pAxD) have emerged as a major pathophysiological driver in many neurodegenerative diseases. Consequently, a central therapeutic focus is to develop approaches tailored to protect axons. A prerequisite for such therapies is a better understanding of the autonomous and non- cell autonomous molecular mechanisms that regulate the processes leading to pAxD. Physical disconnection of the axon from the neuronal cell body is a widely-used experimental platform that has dramatically improved our understanding of these processes over the last two decades. Primarily studied in the peripheral nervous system of vertebrates, this paradigm triggers early injury responses in Schwann cells followed by rapid and stereotyped disintegration of axons (Wallerian degeneration). It is now known that axon disintegration is evoked by a conserved auto-destruction program that exhausts axonal ATP content through rapid depletion of the metabolic cofactor NAD+ in disconnected axons. Importantly, recent studies indicate an instructive role of axonal bioenergetics for the survival of injured axons. Given that neurodegenerative diseases are broadly associated with axonal bioenergetic defects, these findings suggest that the decline of axonal bioenergetics occupies a central position in the pathway leading to pAxD. In support of this, we recently made the exciting discovery that Schwann cells convert their energy metabolism early upon axon injury to antagonize the structural breakdown of injured axons, likely through the increased supply of glycolytic end-products (axon-glia metabolic coupling). Furthermore, we found that the manipulation of the metabolic injury adaptation in Schwann cells accelerates or delays the degeneration of perturbed axons in acute and subacute pAxD models. For the first time, this demonstrates a non-cell-autonomous energetic mechanism that controls the fate of injured axons. The first aim of this proposal attempts to determine if the suggested metabolic coupling mechanism counteracts the energetic decline of injured axons through the enhanced supply of glial manocarboxylates that support axonal ATP production. The next objective extends the identification of the key components of the metabolic coupling pathway critical for the support of injured axons with an emphasis on axonal mitochondria. The final goal intends to examine as to how manipulation of metabolic coupling influences pAxD in an iatrogenic disease model of subacute axon pertubation. Collectively, this work has the potential to introduce a paradigm shift away from neuron-centric views of axon protection. The proposed efforts may open the door for the future development of novel therapeutic approaches taking into account the relationship between axonal and glial bioenergetics to combat pAxD in neurodegenerative disorders. .