His36Pro point-mutated proteolipid protein retained in the endoplasmic reticulum of oligodendrocytes in the shaking pup.
The shaking pup (shp) is a canine mutation that affects the myelin protein proteolipid protein (PLP) and its smaller and less abundant isoform, DM20, with proline replacing histidine(36), resulting in a severe myelin deficiency in the central nervous system. We present evidence that the mutation leads to disrupted trafficking of the shp PLP/DM20 within oligodendrocytes. Immunohistochemical studies revealed significantly reduced levels of PLP/DM20 and other major myelin components such as myelin basic protein (MBP), myelin associated glycoprotein (MAG), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in shp myelin. The distribution of shp PLP/DM20 proteins were altered and mostly retained in perinuclear cytoplasm and proximal processes, which co-localized with distended rough endoplasmic reticulum (RER) within oligodendrocytes. No abnormal accumulation of MAG, MBP, or CNP in the cell body was found. These results suggest that mutated PLP/DM20 in the shp could be selectively retained in RER, causing disruption of their translocation to the periphery to myelinate axons.
Song
Jonathan
J
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706, USA. jsong@med.wayne.edu
Goetz
Brian D
BD
Duncan
Ian D
ID
D019943:Amino Acid Substitution; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D006639:Histidine / Q000502:physiology*; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism* / Q000648:ultrastructure; D017354:Point Mutation / Q000502:physiology*; D011392:Proline / Q000502:physiology*; D011510:Proteolipids / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology
D011510:Proteolipids; D006639:Histidine; D011392:Proline