Proteolipid Protein Gene Mutation Induces Altered Ventilatory Response to Hypoxia in the Myelin-Deficient Rat

Abstract

Pelizaeus Merzbacher disease is an X-linked dysmyelinating disorder of the CNS, resulting from mutations in the proteolipid protein (PLP) gene. An animal model for this disorder, the myelin-deficient (MD) rat, carries a point mutation in the PLP gene and exhibits a phenotype similar to the fatal, connatal disease, including extensive dysmyelination, tremors, ataxia, and death at approximately postnatal day 21 (P21). We postulated that early death might result from disruption of myelinated neural pathways in the caudal brainstem and altered ventilatory response to oxygen deprivation or hypercapnic stimulus. Using barometric plethysmography to measure respiratory function, we found that the MD rat develops lethal hypoxic depression of breathing at P21, but hypercapnic ventilatory response is normal. Histologic examination of the caudal brainstem in the MD rat at this age showed extensive dysmyelination and downregulation of NMDA and to a lesser extent GABA(A) receptors on neurons in the nucleus tractus solitarius, hypoglossal nucleus, and dorsal motor nucleus of the vagus. Unexpectedly, immunoreactive PLP/DM20 was detected in neurons in the caudal brainstem. Not all biosynthetic functions and structural elements were altered in these neurons, because phosphorylated and nonphosphorylated neurofilament and choline acetyltransferase expression were comparable between MD and wild-type rats. These findings suggest that PLP is expressed in neurons in the developing brainstem and that PLP gene mutation can selectively disrupt central processing of afferent neural input from peripheral chemoreceptors, leaving the central chemosensory system for hypercapnia intact.

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

“…9F) and Xenopus and shark brains. Staining of rat caudal brainstem neurons with this mAb has also previously been demonstrated (Miller et al, 2003). This PLP region has from approximately 33% to 61% identity with most of the known M6 and DM sequences and with the Rhombex-29 sequence (Supplemental Table C).…”

“…9D,E) and anti-264-276 mAbs stained small numbers of neurons in the ventral brainstem of mammals and the barn owl. There is a relatively high degree of sequence identity with rat Rhombex-29 in these PLP regions, suggesting that the stained neurons might be a specific chemosensitive Rhombex-29-expressing population (Miller et al, 2003;Shimokawa et al, 2005). On the other hand, M6 proteins, particularly M6a, are abundant in mature neurons in the cerebellar granular layer (Yan et al, 1993(Yan et al, , 1996Roussel et al, 1998), and we did not observe widespread staining in that anatomic region with any of the mAbs, suggesting that they might not recognize M6a protein epitopes.…”

Glutamate Stimulates Oligodendrocyte Progenitor Migration Mediated via an αvIntegrin/Myelin Proteolipid Protein Complex

“…The consensus was that PLP functioned as a structural component of myelin, providing stability and maintaining the compact lamellar structure of myelin. Emerging data demonstrate the importance of PLP expression during early brain development in OPCs and neurons (Timsit et al, 1992;Mallon et al, 2002;Miller et al, 2003), as well as in non-neural cells (Skoff et al, 2004). Moreover, a soma-restricted alternatively spliced isoform of PLP was detected in motor neurons and striated muscle before the onset of myelination (Jacobs et al, 2004).…”

Expression of a Myelin Proteolipid Protein (Plp)-lacZ Transgene is Reduced in both the CNS and PNS of Plp jp Mice

“…Mutant PLP proteins tend to accumulate in the endoplasmic reticulum of oligodendrocyte cell bodies [9], and it is proposed that the defective protein activates the unfolded protein response, culminating in oligodendrocyte cell death [10]. The greater lethality of these mutations, however, likely results from expression of mutated PLP in neurons in the brainstem, which leads to dramatic respiratory depression in response to hypoxia [11].…”