PMID- 20886109
OWN - NLM
STAT- MEDLINE
DCOM- 20110218
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 9
DP  - 2010 Sep 23
TI  - Catalytic function of PLA2G6 is impaired by mutations associated with infantile 
      neuroaxonal dystrophy but not dystonia-parkinsonism.
PG  - e12897
LID - e12897 [pii]
LID - 10.1371/journal.pone.0012897 [doi]
AB  - BACKGROUND: Mutations in the PLA2G6 gene have been identified in autosomal 
      recessive neurodegenerative diseases classified as infantile neuroaxonal 
      dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and 
      dystonia-parkinsonism. These clinical syndromes display two significantly 
      different disease phenotypes. NBIA and INAD are very similar, involving 
      widespread neurodegeneration that begins within the first 1-2 years of life. In 
      contrast, patients with dystonia-parkinsonism present with a parkinsonian 
      movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the 
      PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A(2), 
      which has previously been shown to hydrolyze the sn-2 acyl chain of 
      phospholipids, generating free fatty acids and lysophospholipids. 
      METHODOLOGY/PRINCIPAL FINDINGS: We produced purified recombinant wildtype (WT) 
      and mutant human PLA2G6 proteins and examined their catalytic function using in 
      vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme 
      hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. 
      Mutations associated with different disease phenotypes have different effects on 
      catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme 
      activity, with mutant proteins exhibiting less than 20% of the specific activity 
      of WT protein in both lysophospholipase and phospholipase assays. In contrast, 
      mutations associated with dystonia-parkinsonism do not impair catalytic activity, 
      and two mutations produce a significant increase in specific activity for 
      phospholipid but not lysophospholipid substrates. CONCLUSIONS/SIGNIFICANCE: These 
      results indicate that different alterations in PLA2G6 function produce the 
      different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is 
      caused by loss of the ability of PLA2G6 to catalyze fatty acid release from 
      phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and 
      provides a mechanistic explanation for the accumulation of membranes in 
      neuroaxonal spheroids previously observed in histopathological studies of 
      INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly 
      impair catalytic function, but may modify substrate preferences or regulatory 
      mechanisms for PLA2G6.
FAU - Engel, Laura A
AU  - Engel LA
AD  - Department of Neurology, Hope Center for Neurological Disorders, Washington 
      University School of Medicine, St. Louis, Missouri, United States of America.
FAU - Jing, Zheng
AU  - Jing Z
FAU - O'Brien, Daniel E
AU  - O'Brien DE
FAU - Sun, Mengyang
AU  - Sun M
FAU - Kotzbauer, Paul T
AU  - Kotzbauer PT
LA  - eng
GR  - K08 NS048924/NS/NINDS NIH HHS/United States
GR  - NS48924-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100923
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (PLA2G6 protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Catalysis
MH  - Dystonia/*enzymology/genetics
MH  - Group VI Phospholipases A2/chemistry/*genetics/*metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Neuroaxonal Dystrophies/*enzymology/genetics
MH  - Parkinsonian Disorders/*enzymology/genetics
PMC - PMC2944820
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/10/05 06:00
MHDA- 2011/02/22 06:00
PMCR- 2010/09/23
CRDT- 2010/10/02 06:00
PHST- 2010/05/03 00:00 [received]
PHST- 2010/08/31 00:00 [accepted]
PHST- 2010/10/02 06:00 [entrez]
PHST- 2010/10/05 06:00 [pubmed]
PHST- 2011/02/22 06:00 [medline]
PHST- 2010/09/23 00:00 [pmc-release]
AID - e12897 [pii]
AID - 10-PONE-RA-18564R1 [pii]
AID - 10.1371/journal.pone.0012897 [doi]
PST - epublish
SO  - PLoS One. 2010 Sep 23;5(9):e12897. doi: 10.1371/journal.pone.0012897.