Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves

Abstract

Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4 + and CD8 + T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders.

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

“…The PH domain has been shown to regulate the RhoGEF domain. Plekhg5 inactivation in a murine model results in a late-onset motoneuron disease with degeneration of axon terminals [16] but also defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves [19]. Moreover, aggregate formation have been observed in mutant Plekhg5 murine motoneurons [3].…”

Restoring Functional Behaviors After Traumatic Peripheral Nerve Injuries

“…Unlike the classical activation of autophagy, which relies on the inhibition of the mTOR pathway, autophagy in SCs is activated by an mTOR-independent mechanism that is regulated by the actions of ceramides on the JNK/c-Jun pathway (114,118,137). Activation of this pathway may be synergistic with the inhibitory effect of c-Jun on myelin-associated protein expression in response to acute injury.…”

Review: Myelin clearance is critical for regeneration after peripheral nerve injury

“…Notably, lipids represent 70-80% of the composition of peripheral myelin (116) and lipid droplets have been detected as autophagic cargo (117). Therefore, autophagy is a crucial process involved in nerve repair; impaired autophagy results in reductions in both myelin degradation and remyelination (118).…”