PMID- 22008564
OWN - NLM
STAT- MEDLINE
DCOM- 20120319
LR  - 20211020
IS  - 1476-511X (Electronic)
IS  - 1476-511X (Linking)
VI  - 10
DP  - 2011 Oct 18
TI  - In vitro and in vivo plasmalogen replacement evaluations in rhizomelic 
      chrondrodysplasia punctata and Pelizaeus-Merzbacher disease using PPI-1011, an 
      ether lipid plasmalogen precursor.
PG  - 182
LID - 10.1186/1476-511X-10-182 [doi]
AB  - BACKGROUND: Childhood peroxisomal disorders and leukodystrophies are devastating 
      diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether 
      glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The 
      biosynthesis of plasmalogens is initiated in peroxisomes but completed in the 
      endoplasmic reticulum. We therefore undertook a study to evaluate the ability of 
      a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace 
      plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and 
      rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess 
      peroxisomal mutations culminating in deficient plasmalogen synthesis. We also 
      examined plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes 
      which possess a proteolipid protein-1 (PLP1) missense mutation that results in 
      abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), 
      the cellular site of the last steps in plasmalogen synthesis. In vivo 
      incorporation of plasmalogen precursor into tissue plasmalogens was also 
      evaluated in the Pex7 mouse model of plasmalogen deficiency. RESULTS: In both 
      RCDP1 and RCDP2 lymphocytes, PPI-1011 repleted the target ethanolamine 
      plasmalogen (PlsEtn16:0/22:6) in a concentration dependent manner. In addition, 
      deacylation/reacylation reactions resulted in repletion of PlsEtn 16:0/20:4 in 
      both RCDP1 and RCDP2 lymphocytes, repletion of PlsEtn 16:0/18:1 and PlsEtn 
      16:0/18:2 in RCDP2 lymphocytes, and partial repletion of PlsEtn 16:0/18:1 and 
      PlsEtn 16:0/18:2 in RCDP1 lymphocytes. In the Pex7 mouse, oral dosing of labeled 
      PPI-1011 demonstrated repletion of tissue levels of the target plasmalogen PlsEtn 
      16:0/22:6 with phospholipid remodeling also resulting in significant repletion of 
      PlsEtn 16:0/20:4 and PlsEtn 16:0/18:1. Metabolic conversion of PPI-1011 to the 
      target plasmalogen was most active in the liver. CONCLUSIONS: Our data 
      demonstrate that PPI-1011 is activated (removal of 3-substitution) and converted 
      to PlsEtn in vitro in both RCDP1 and RCDP2 lymphocytes and in vivo in the Pex7 
      mouse model of RCPD1 effectively bypassing the peroxisomal dysfunction present in 
      these disorders. While PPI-1011 was shown to replete PlsEtns 16:0/x, ether lipid 
      precursors of PlsEtn 18:0/x and PlsEtn 18:1/x may also be needed to achieve 
      optimal clinical benefits of plasmalogen replacement in these complex patient 
      populations. In contrast, only limited plasmalogen replacement was observed in 
      PMD lymphocytes suggesting that the effects of protein misfolding and 
      accumulation in the ER negatively affect processing of plasmalogen precursors in 
      this cellular compartment.
FAU - Wood, Paul L
AU  - Wood PL
AD  - Dept, of Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial 
      University, 6965 Cumberland Gap Parkway, Harrogate, TN 37752, USA. 
      paul.wood@lmunet.edu
FAU - Khan, M Amin
AU  - Khan MA
FAU - Smith, Tara
AU  - Smith T
FAU - Ehrmantraut, Greg
AU  - Ehrmantraut G
FAU - Jin, Wei
AU  - Jin W
FAU - Cui, Wei
AU  - Cui W
FAU - Braverman, Nancy E
AU  - Braverman NE
FAU - Goodenowe, Dayan B
AU  - Goodenowe DB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111018
PL  - England
TA  - Lipids Health Dis
JT  - Lipids in health and disease
JID - 101147696
RN  - 0 (Diglycerides)
RN  - 0 (PEX7 protein, human)
RN  - 0 (Peroxisomal Targeting Signal 2 Receptor)
RN  - 0 (Plasmalogens)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (phosphatidal ethanolamines)
RN  - Rhizomelic chondrodysplasia punctata, type 1
RN  - Rhizomelic chondrodysplasia punctata, type 2
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chondrodysplasia Punctata, Rhizomelic/*metabolism
MH  - Diglycerides/*pharmacology
MH  - Eye/metabolism
MH  - Humans
MH  - Kidney/metabolism
MH  - Lymphocytes/*drug effects/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Neocortex/metabolism
MH  - Pelizaeus-Merzbacher Disease/genetics/*metabolism
MH  - Peroxisomal Targeting Signal 2 Receptor
MH  - Plasmalogens/biosynthesis/*metabolism
MH  - Receptors, Cytoplasmic and Nuclear/genetics
MH  - Tissue Distribution
PMC - PMC3238230
EDAT- 2011/10/20 06:00
MHDA- 2012/03/20 06:00
PMCR- 2011/10/18
CRDT- 2011/10/20 06:00
PHST- 2011/08/09 00:00 [received]
PHST- 2011/10/18 00:00 [accepted]
PHST- 2011/10/20 06:00 [entrez]
PHST- 2011/10/20 06:00 [pubmed]
PHST- 2012/03/20 06:00 [medline]
PHST- 2011/10/18 00:00 [pmc-release]
AID - 1476-511X-10-182 [pii]
AID - 10.1186/1476-511X-10-182 [doi]
PST - epublish
SO  - Lipids Health Dis. 2011 Oct 18;10:182. doi: 10.1186/1476-511X-10-182.