Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation

Abstract

Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin protein, proteolipid protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-acetyl aspartate (NAA), a marker of axonal integrity. Length-dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients' brain tissue also demonstrated a length-dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin protein PLP1. This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1-mediated axonal--glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

“…3,19 Consequently, a loss-of-function mutation of PLP1 does not induce oligodendrocyte cell death, possibly serving as a mechanism underlying the milder phenotypic consequences observed in patients with null PLP1 mutations. Although length-dependent axonal degeneration has been described in PLP1 null mutations, 20 there is no information about peripheral neuropathy in Patient 1. Thus, it was unclear whether the clinical condition of Patient 1 is compatible with that of PLP1 null mutations.…”

The myelin proteolipid protein gene modulates apoptosis in neural and non-neural tissues

“…21,38 Similarly in PelizaeusMerzbacher patients lacking PLP, CNS myelination is fairly normal and death does not begin until men are in their 30s. 14,38 In contrast, modest overexpression of the native proteolipid protein gene (PLP/Plp) in man and in transgenic mice is almost always lethal, with death in some males by their second year. 39 Nearly a hundred Plp mutations have been described in animals almost all of which are lethal (http:// www.med.wayne.edu/Neurology/plp.html.).…”

“…11 This finding is mimicked in vivo where either modest overexpression of native PLP or its absence leads to axonal abnormalities and neuronal death. [12][13][14] Thus, regulation of the level of native PLP in vivo is critical as deviation from baseline levels leads to both glial and neuronal abnormalities. We show for the first time that PLP is expressed in non-neural cells during normal development, and that its level of expression correlates with the amount of apoptosis.…”

Hereditary Spastic Paraplegia: Clues from a Rare Disorder for a Common Problem?

“…Furthermore, alterations of the unfolded protein response, a pathway linking protein trafficking to transcriptional and translational control, have been recently demonstrated in the above spontaneous mouse models as well as in fibroblasts with PLP1 mutations (22). The pattern of axonal involvement after PLP1 mutations is clearly dependent on axonal length, and a length-dependent axonal degeneration has been demonstrated in PLPI null mice and in patients with PLP1 deficiency (23). In addition to the well-known changes in myelin function, developmental abnormalities may be subtle ones, as well as processes within neurons themselves which are now suggested to play a role in the pathogenesis of PLP1 induced neurodegeneration.…”