PLP1-related Inherited Dysmyelinating Disorders: Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type 2

Overview

Journal Neurogenetics

Specialty Neurology

Date 2005 Jan 1

PMID 15627202

Citations 98

Authors

Ken Inoue

Affiliations

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Abstract

Pelizaeus-Merzbacher disease (PMD) and its allelic disorder, spastic paraplegia type 2 (SPG2), are among the best-characterized dysmyelinating leukodystrophies of the central nervous system (CNS). Both PMD and SPG2 are caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major component of CNS myelin proteins. Distinct types of mutations, including point mutations and genomic duplications and deletions, have been identified as causes of PMD/SPG2 that act through different molecular mechanisms. Studies of various PLP1 mutants in humans and animal models have shed light on the genomic, molecular, and cellular pathogeneses of PMD/SPG2. Recent discoveries include complex mutational mechanisms and associated disease phenotypes, novel cellular pathways that lead to the degeneration of oligodendrocytes, and genomic architectural features that result in unique chromosomal rearrangements. Here, I review the previous and current knowledge of the molecular pathogenesis of PMD/SPG2 and delineate future directions for PMD/SPG2 studies.

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References

Barkovich A . Concepts of myelin and myelination in neuroradiology. AJNR Am J Neuroradiol. 2000; 21(6):1099-109. PMC: 7973874. View

Gencic S, Hudson L . Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice. J Neurosci. 1990; 10(1):117-24. PMC: 6570349. View

Lu Q, Yuk D, Alberta J, Zhu Z, Pawlitzky I, Chan J . Sonic hedgehog--regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron. 2000; 25(2):317-29. DOI: 10.1016/s0896-6273(00)80897-1. View

Bongarzone E, Campagnoni C, Kampf K, JACOBS E, Handley V, Schonmann V . Identification of a new exon in the myelin proteolipid protein gene encoding novel protein isoforms that are restricted to the somata of oligodendrocytes and neurons. J Neurosci. 1999; 19(19):8349-57. PMC: 6783048. View

Bonavita S, Schiffmann R, Moore D, Frei K, Choi B, Patronas MD N . Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology. 2001; 56(6):785-8. DOI: 10.1212/wnl.56.6.785. View

Spalice A, Popolizio T, Parisi P, Scarabino T, Iannetti P . Proton MR spectroscopy in connatal Pelizaeus-Merzbacher disease. Pediatr Radiol. 2001; 30(3):171-5. DOI: 10.1007/s002470050039. View

Simons M, Kramer E, Thiele C, STOFFEL W, Trotter J . Assembly of myelin by association of proteolipid protein with cholesterol- and galactosylceramide-rich membrane domains. J Cell Biol. 2000; 151(1):143-54. PMC: 2189802. DOI: 10.1083/jcb.151.1.143. View

Southwood C, Garbern J, Jiang W, Gow A . The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron. 2002; 36(4):585-96. PMC: 4603660. DOI: 10.1016/s0896-6273(02)01045-0. View

Fink J . The hereditary spastic paraplegias: nine genes and counting. Arch Neurol. 2003; 60(8):1045-9. DOI: 10.1001/archneur.60.8.1045. View

10.

Pingault V, Girard M, Bondurand N, Dorkins H, Van Maldergem L, Mowat D . SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism. Hum Genet. 2002; 111(2):198-206. DOI: 10.1007/s00439-002-0765-8. View

11.

Gow A, Southwood C, Lazzarini R . Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease. J Cell Biol. 1998; 140(4):925-34. PMC: 2141744. DOI: 10.1083/jcb.140.4.925. View

12.

Edgar J, McLaughlin M, Yool D, Zhang S, Fowler J, Montague P . Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol. 2004; 166(1):121-31. PMC: 2172145. DOI: 10.1083/jcb.200312012. View

13.

Lupski J . Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 1998; 14(10):417-22. DOI: 10.1016/s0168-9525(98)01555-8. View

14.

Toki F, Suzuki N, Inoue K, Suzuki M, Hirakata K, Nagai K . Intestinal aganglionosis associated with the Waardenburg syndrome: report of two cases and review of the literature. Pediatr Surg Int. 2003; 19(11):725-8. DOI: 10.1007/s00383-003-1057-7. View

15.

Stecca B, Southwood C, Gragerov A, Kelley K, Friedrich Jr V, Gow A . The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin. J Neurosci. 2000; 20(11):4002-10. PMC: 6772626. View

16.

Mitome M, Low H, van den Pol A, Nunnari J, Wolf M, Billings-Gagliardi S . Towards the reconstruction of central nervous system white matter using neural precursor cells. Brain. 2001; 124(Pt 11):2147-61. DOI: 10.1093/brain/124.11.2147. View

17.

Yan Y, Lagenaur C, Narayanan V . Molecular cloning of M6: identification of a PLP/DM20 gene family. Neuron. 1993; 11(3):423-31. DOI: 10.1016/0896-6273(93)90147-j. View

18.

Sereda M, Meyer Zu Horste G, Suter U, Uzma N, Nave K . Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med. 2003; 9(12):1533-7. DOI: 10.1038/nm957. View

19.

Gow A, Sharma R . The unfolded protein response in protein aggregating diseases. Neuromolecular Med. 2003; 4(1-2):73-94. DOI: 10.1385/NMM:4:1-2:73. View

20.

Jacobs E, Bongarzone E, Campagnoni C, Campagnoni A . Embryonic expression of the soma-restricted products of the myelin proteolipid gene in motor neurons and muscle. Neurochem Res. 2004; 29(5):997-1002. DOI: 10.1023/b:nere.0000021244.38279.c4. View