Arrest of proteolipid transport through the Golgi apparatus in Jimpy brain

Abstract

Immunocytochemical investigations were performed on Jimpy and control mouse brains using three specific anti-myelin proteolipids antisera: immunoaffinity purified multivalent anti-(PLP + DM-20) proteolipid antibodies, anti-C-terminal hexapeptide 271-276 and anti-tridecapeptide 117-129 antisera. The results show that oligodendrocytes and myelin sheaths in normal mouse brain are labelled to the same extent by the three specific antisera; in contrast, in Jimpy brain these cellular structures are only stained by the multivalent antibodies and the site-specific, anti-tridecapeptide antiserum. The absence of labelling with C-terminal hexapeptide antiserum in mutant brain is interpreted as the result of either a large deletion or a point mutation producing a frameshift in the C-terminal part of the sequences of the proteolipids PLP and DM-20. Furthermore, we show that this mutation prevents the normal transport of proteolipid molecules through the Golgi apparatus. The existence of a minor, extra-Golgi apparatus metabolic route for proteolipids to myelin structures is also discussed.

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

“…PLP and DM20 proteins are processed through the endoplasmic reticulum (ER) and Golgi membranes. Thus, as reported in other studies, the mutant proteins encoded by the Plp jp gene likely cannot fold correctly and are prevented from moving further through the intracellular transport pathway [9,45]. As mentioned earlier, the PLP(+)Z transgene encodes a protein that contains the 13 N-terminal amino acids of PLP/DM20.…”

Myelin Proteolipid Protein (PLP), but Not DM-20, Is an Inositol Hexakisphosphate-binding Protein

“…Mutations within the PLP gene causes severe dysmyelination (8), at least in part caused by an impaired protein transport system. In one of the PLP mutants, the jimpy mouse, for example, the mutated PLP protein accumulates in the rough endoplasmic reticulum and very little PLP is found in myelin (6). In oligodendrocytes of the transgenic mouse overexpressing the wild type PLP gene there is a swelling in the Golgi apparatus and PLP is rarely found in myelin (9,10).…”

“…InsP 6 is found at concentrations from 10 to 100 M in many kinds of cells (15,16). Although, the function of InsP 6 has not yet been clarified, several recent findings have suggested a physiological role for InsP 6 .…”

Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid.

“…The mutation may prevent the correct folding of PLP and DM20 by steric hindrance, or by reinforcing the rather high hydrophobicity of this region of the sequence. Alternatively, it may interfere with homologous or heterologous interactions in the endoplasmic reticulum membrane, which could perturb export to the Golgi apparatus and the plasma membrane as observed with the jimpy mutant (30). Finally, the Pro215 Ser mutation (10) -28).…”