PMID- 18202189
OWN - NLM
STAT- MEDLINE
DCOM- 20080408
LR  - 20220318
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 172
IP  - 2
DP  - 2008 Feb
TI  - Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a 
      mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations.
PG  - 406-16
LID - 10.2353/ajpath.2008.070823 [doi]
AB  - Mutations in the PLA2G6 gene, which encodes group VIA calcium-independent 
      phospholipase A2 (iPLA(2)beta), were recently identified in patients with 
      infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron 
      accumulation. A pathological hallmark of these childhood neurodegenerative 
      diseases is the presence of distinctive spheroids in distal axons that contain 
      accumulated membranes. We used iPLA(2)beta-KO mice generated by homologous 
      recombination to investigate neurodegenerative consequences of PLA2G6 mutations. 
      iPLA(2)beta-KO mice developed age-dependent neurological impairment that was 
      evident in rotarod, balance, and climbing tests by 13 months of age. The primary 
      abnormality underlying this neurological impairment was the formation of 
      spheroids containing tubulovesicular membranes remarkably similar to human INAD. 
      Spheroids were strongly labeled with anti-ubiquitin antibodies. Accumulation of 
      ubiquitinated protein in spheroids was evident in some brain regions as early as 
      4 months of age, and the onset of motor impairment correlated with a dramatic 
      increase in ubiquitin-positive spheroids throughout the neuropil in nearly all 
      brain regions. Furthermore accumulating ubiquitinated proteins were observed 
      primarily in insoluble fractions of brain tissue, implicating protein aggregation 
      in this pathogenic process. These results indicate that loss of iPLA(2)beta 
      causes age-dependent impairment of axonal membrane homeostasis and protein 
      degradation pathways, leading to age-dependent neurological impairment. 
      iPLA(2)beta-KO mice will be useful for further studies of pathogenesis and 
      experimental interventions in INAD and neurodegeneration with brain iron 
      accumulation.
FAU - Malik, Ibrahim
AU  - Malik I
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Turk, John
AU  - Turk J
FAU - Mancuso, David J
AU  - Mancuso DJ
FAU - Montier, Laura
AU  - Montier L
FAU - Wohltmann, Mary
AU  - Wohltmann M
FAU - Wozniak, David F
AU  - Wozniak DF
FAU - Schmidt, Robert E
AU  - Schmidt RE
FAU - Gross, Richard W
AU  - Gross RW
FAU - Kotzbauer, Paul T
AU  - Kotzbauer PT
LA  - eng
GR  - P30 NS057105/NS/NINDS NIH HHS/United States
GR  - R37 DK034388/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341-08/DK/NIDDK NIH HHS/United States
GR  - R37-DK34388/DK/NIDDK NIH HHS/United States
GR  - P60 DK020579/DK/NIDDK NIH HHS/United States
GR  - NS48924-01/NS/NINDS NIH HHS/United States
GR  - K08 NS048924/NS/NINDS NIH HHS/United States
GR  - P60-DK20579/DK/NIDDK NIH HHS/United States
GR  - NS057105/NS/NINDS NIH HHS/United States
GR  - 5P01HL57278/HL/NHLBI NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341-07/DK/NIDDK NIH HHS/United States
GR  - P01 HL057278/HL/NHLBI NIH HHS/United States
GR  - P41 RR000954/RR/NCRR NIH HHS/United States
GR  - P41-RR00954/RR/NCRR NIH HHS/United States
GR  - P30-DK56341/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080117
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (PLA2G6 protein, human)
SB  - IM
MH  - Animals
MH  - Axons/ultrastructure
MH  - Brain/*pathology
MH  - *Disease Models, Animal
MH  - Gait Disorders, Neurologic/etiology
MH  - Group VI Phospholipases A2/*genetics
MH  - Homeostasis
MH  - Immunohistochemistry
MH  - Inclusion Bodies/*ultrastructure
MH  - Lameness, Animal/etiology
MH  - Membranes/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Electron, Transmission
MH  - Mutation
MH  - Neuroaxonal Dystrophies/genetics/*pathology/physiopathology
MH  - *Ubiquitination
PMC - PMC2312364
EDAT- 2008/01/19 09:00
MHDA- 2008/04/09 09:00
PMCR- 2008/08/01
CRDT- 2008/01/19 09:00
PHST- 2008/01/19 09:00 [pubmed]
PHST- 2008/04/09 09:00 [medline]
PHST- 2008/01/19 09:00 [entrez]
PHST- 2008/08/01 00:00 [pmc-release]
AID - S0002-9440(10)61807-X [pii]
AID - 10.2353/ajpath.2008.070823 [doi]
PST - ppublish
SO  - Am J Pathol. 2008 Feb;172(2):406-16. doi: 10.2353/ajpath.2008.070823. Epub 2008 
      Jan 17.