PMID- 25950622
OWN - NLM
STAT- MEDLINE
DCOM- 20160219
LR  - 20150602
IS  - 1440-1789 (Electronic)
IS  - 0919-6544 (Linking)
VI  - 35
IP  - 3
DP  - 2015 Jun
TI  - Neuroaxonal dystrophy in PLA2G6 knockout mice.
PG  - 289-302
LID - 10.1111/neup.12202 [doi]
AB  - The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 (iPLA2 beta), 
      which belongs to the PLA2 superfamily that hydrolyses the sn-2 ester bond in 
      phospholipids. In the nervous system, iPLA2 beta is essential for remodeling 
      membrane phospholipids in axons and synapses. Mutated PLA2G6 causes 
      PLA2G6-associated neurodegeneration (PLAN) including infantile neuroaxonal 
      dystrophy (INAD) and adult-onset dystonia-parkinsonism (PARK14), which have 
      unique clinical phenotypes. In the PLA2G6 knockout (KO) mouse, which is an 
      excellent PLAN model, specific membrane degeneration takes place in neurons and 
      their axons, and this is followed by axonal spheroid formation. These 
      pathological findings are similar to those in PLAN. This review details the 
      evidence that membrane degeneration of mitochondria and axon terminals is a 
      precursor to spheroid formation in this disease model. From a young age before 
      the onset, many mitochondria with damaged inner membranes appear in PLA2G6 KO 
      mouse neurons. These injured mitochondria move anterogradely within the axons, 
      increasing in the distal axons. As membrane degeneration progresses, the collapse 
      of the double membrane of mitochondria accompanies axonal injury near impaired 
      mitochondria. At the axon terminals, the membranes of the presynapses expand 
      irregularly from a young age. Over time, the presynaptic membrane ruptures, 
      causing axon terminal degeneration. Although these processes occur in different 
      degenerating membranes, both contain tubulovesicular structures, which are a 
      specific ultrastructural marker of INAD. This indicates that two unique types of 
      membrane degeneration underlie PLAN pathology. We have shown a new pathological 
      mechanism whereby axons degenerate due to defective maintenance and rupture of 
      both the inner mitochondrial and presynaptic membranes. This degeneration 
      mechanism could possibly clarify the pathologies of PLAN, Parkinson disease and 
      neurodegeneration with iron accumulation (NBIA), which are assumed to be due to 
      the primary degeneration of axons.
CI  - (c) 2015 Japanese Society of Neuropathology.
FAU - Sumi-Akamaru, Hisae
AU  - Sumi-Akamaru H
AD  - Department of Neurology, Osaka University Graduate School of Medicine, Suita, 
      Japan.
FAU - Beck, Goichi
AU  - Beck G
AD  - Department of Neurology, Osaka University Graduate School of Medicine, Suita, 
      Japan.
FAU - Kato, Shinsuke
AU  - Kato S
AD  - Division of Neuropathology, Department of Brain and Neurosciences, Tottori 
      University Faculty of Medicine, Yonago, Japan.
FAU - Mochizuki, Hideki
AU  - Mochizuki H
AD  - Department of Neurology, Osaka University Graduate School of Medicine, Suita, 
      Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20150506
PL  - Australia
TA  - Neuropathology
JT  - Neuropathology : official journal of the Japanese Society of Neuropathology
JID - 9606526
RN  - 0 (Glycerophospholipids)
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (Pla2g6 protein, mouse)
SB  - IM
MH  - Animals
MH  - Axons/pathology
MH  - Brain/pathology
MH  - *Disease Models, Animal
MH  - Disease Progression
MH  - Glycerophospholipids/metabolism
MH  - Group VI Phospholipases A2/*genetics
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/ultrastructure
MH  - Neuroaxonal Dystrophies/*genetics/metabolism/*pathology
MH  - Neurons/ultrastructure
MH  - Oxidative Stress
MH  - Peripheral Nerves/pathology
MH  - Spinal Cord/pathology
OTO - NOTNLM
OT  - PLA2G6
OT  - calcium independent phospholipaseA2beta (iPLA2beta)
OT  - infantile neuroaxonal dystrophy (INAD)
OT  - membrane
OT  - mitochondria
EDAT- 2015/05/08 06:00
MHDA- 2016/02/20 06:00
CRDT- 2015/05/08 06:00
PHST- 2015/01/01 00:00 [received]
PHST- 2015/01/25 00:00 [accepted]
PHST- 2015/05/08 06:00 [entrez]
PHST- 2015/05/08 06:00 [pubmed]
PHST- 2016/02/20 06:00 [medline]
AID - 10.1111/neup.12202 [doi]
PST - ppublish
SO  - Neuropathology. 2015 Jun;35(3):289-302. doi: 10.1111/neup.12202. Epub 2015 May 6.