Evolution of a neuroprotective function of central nervous system myelin.
The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when a tetraspan membrane protein, myelin proteolipid protein (PLP), replaced the type I integral membrane protein, P0, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P0 instead of PLP in CNS myelin. In the absence of PLP, the ancestral P0 provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P0 is the major structural protein today. The PLP-P0 shift resulted in reduced myelin internode length, degeneration of myelinated axons, severe neurological disability, and a 50% reduction in lifespan. Mice with equal amounts of P0 and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia.
Yin
Xinghua
X
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Baek
Rena C
RC
Kirschner
Daniel A
DA
Peterson
Alan
A
Fujii
Yasuhisa
Y
Nave
Klaus-Armin
KA
Macklin
Wendy B
WB
Trapp
Bruce D
BD
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019143:Evolution, Molecular; D005080:Exercise Test; D015870:Gene Expression / Q000235:genetics; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009043:Motor Activity / Q000235:genetics; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D018993:Myelin P0 Protein / Q000235:genetics* / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics* / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018992:Myelin-Associated Glycoprotein; D009836:Oligodendroglia / Q000378:metabolism; D009900:Optic Nerve / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014961:X-Ray Diffraction
D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; C104739:Mag protein, mouse; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D011956:Receptors, Cell Surface; D015222:Sodium Channels; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse