A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.

Shackleford, Ghjuvan'Ghjacumu; Marziali, Leandro N.; Sasaki, Yo; Claessens, Anke; Ferri, Cinzia; Weinstock, Nadav I.; Rossor, Alexander M.; Silvestri, Nicholas J.; Wilson, Emma R.; Hurley, Edward; Kidd, Grahame J.; Manohar, Senthilvelan; Ding, Dalian; Salvi, Richard J.; Feltri, M. Laura; D'Antonio, Maurizio; Wrabetz, Lawrence

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons. Author summary: Charcot-Marie-Tooth (CMT) neuropathies are a large family of incurable peripheral nerve disorders. Despite extensive clinical and genetic heterogeneity, axonal degeneration is the common end point of all the type of CMT. Thus, a major question is why axons degenerate and how to protect them. Over the years, it has become clear that myelinating glial cells, which are in close contact with axons, are essential for axonal support. However how glial cells support axons remains only partially understood. Here, we generated and characterized an animal model of Charcot-Marie-Tooth 2J (CMT2J), an axonal inherited neuropathy due to mutation in the Myelin Protein Zero (Mpz) gene. Mpz is expressed only in Schwann cells, the peripheral myelin-forming glia, but not in axons, making this the model unique to contribute to our understanding on how glia support axons. Our model reproduces very closely most aspects of the human neuropathy and reveals several alterations in domains crucial for axoglial communication. We also detected metabolic abnormalities in peripheral nerves of these mice that are known to be associated with axonal degeneration. Our work sheds light on the cellular and molecular mechanisms of axoglial communication and axonal degeneration, with implications for a plethora of neurodegenerative diseases.

AXONS; MYELIN proteins; PERIPHERAL nervous system; NEUROGLIA; LABORATORY mice; ACTION potentials; ANIMAL disease models

PLoS Genetics, 2022, Vol 18, Issue 11, p1

1553-7390

Academic Journal

10.1371/journal.pgen.1010477