Disruption of lactate metabolism in the peripheral nervous system leads to motor-selective deficits

Abstract

Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system (PNS) and disruption of SC cellular metabolism leads to demyelination and axon degeneration, both symptoms of peripheral neuropathies. The lactate shuttle hypothesis proposes that glycolytic support cells supply lactate to adjacent axons to sustain their high metabolic demands, a process that requires the interconversion of lactate and pyruvate via lactate dehydrogenase (LDH) in both SCs and neurons. To test this hypothesis in the PNS, we selectively knocked out the genes for both LDH enzymes, LDHA and LDHB, in motor neurons (MNs), sensory neurons (SNs), or SCs. Interestingly, motor axons and their synapses progressively degenerate when LDH is deleted from either MNs or SCs; however, defects in sensory axons or their terminals were not observed when LDH was excised from either SNs or SCs. Deletion of LDH in SCs also leads to a decrease in total ATP levels in peripheral nerves despite a marked accumulation of pyruvate and glycolytic intermediates, consistent with the failure of pyruvate to lactate conversion in SCs leading to energetic deficits in axons. These results support a model in which motor axons are more dependent on SC-derived lactate than are sensory axons, a specific dependency that suggests LDH and lactate shuttling influence the course of motor-dominated neuropathies such as ALS.

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

“…However, Cnp Cre mice also recombine Schwann cells and off‐target in subsets of CNS neurons including motoneuronal precursors (Genoud et al, 2002; Jo et al, 2021; Tognatta et al, 2017) (Figure S1a–e). The deletion of Ldh genes in Schwann cells and motoneurons causes a marked neuropathology (Bloom et al, 2022). Thus, we refrained from the histopathological analysis of brain and spinal cord of Ldha flox/flox ; Ldhb flox/flox ; Cnp Cre double mutant mice (hereafter referred to as dKO, Figure 1a).…”

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

“…Concomitantly, it was recently shown that targeting mitochondria with a small molecule could improve upper motor neuron health in a TDP-43 mouse model (Gautam et al, 2023) . The inability of ALS motor neurons to respond to high energy drains and the lack of compensatory glycolysis could render the motor neurons intrinsically more vulnerable as well as more dependent on glial support (Joseph Bloom et al. ; Lee et al, 2012) .…”

Axolemmal nanoruptures arising from paranodal membrane injury induce secondary axon degeneration in murine Guillain‐Barré syndrome

“…Axons receive energy support via Schwann cells that shuttle lactate via monocarboxylate transporters to the axons 36 . Change in Schwann cell metabolism or lactate shuttling can cause deficits in axonal maintenance 37‐41 . Addition of exogenous L‐Lactate can therefore compensate for deficits in Schwann cell metabolic support to axons 36 .…”

“…36 Change in Schwann cell metabolism or lactate shuttling can cause deficits in axonal maintenance. [37][38][39][40][41] Addition of exogenous L-Lactate can therefore compensate for deficits in Schwann cell metabolic support to axons. 36 We tested this in our model, but lactate supplementation did not attenuate axonal changes.…”