In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 11 ( 2022-11-9), p. e1010477-
Abstract:
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 Mpz T124M 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 Mpz T124M 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 Mpz T124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010477
DOI:
10.1371/journal.pgen.1010477.g001
DOI:
10.1371/journal.pgen.1010477.g002
DOI:
10.1371/journal.pgen.1010477.g003
DOI:
10.1371/journal.pgen.1010477.g004
DOI:
10.1371/journal.pgen.1010477.g005
DOI:
10.1371/journal.pgen.1010477.g006
DOI:
10.1371/journal.pgen.1010477.g007
DOI:
10.1371/journal.pgen.1010477.g008
DOI:
10.1371/journal.pgen.1010477.s001
DOI:
10.1371/journal.pgen.1010477.s002
DOI:
10.1371/journal.pgen.1010477.s003
DOI:
10.1371/journal.pgen.1010477.s004
DOI:
10.1371/journal.pgen.1010477.s005
DOI:
10.1371/journal.pgen.1010477.s006
DOI:
10.1371/journal.pgen.1010477.s007
DOI:
10.1371/journal.pgen.1010477.s008
DOI:
10.1371/journal.pgen.1010477.s009
DOI:
10.1371/journal.pgen.1010477.s010
DOI:
10.1371/journal.pgen.1010477.s011
DOI:
10.1371/journal.pgen.1010477.s012
DOI:
10.1371/journal.pgen.1010477.s013
DOI:
10.1371/journal.pgen.1010477.s014
DOI:
10.1371/journal.pgen.1010477.s015
DOI:
10.1371/journal.pgen.1010477.r001
DOI:
10.1371/journal.pgen.1010477.r002
DOI:
10.1371/journal.pgen.1010477.r003
DOI:
10.1371/journal.pgen.1010477.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2186725-2
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