title: Progressive Axonal Degeneration of Nigrostriatal Dopaminergic Neurons in Calcium-Independent Phospholipase A2β Knockout Mice.
abstract: Calcium-independent phospholipase A2β (iPLA2β, PLA2G6) is essential for the remodeling of membrane glycerophospholipids. Mutations in this gene are responsible for autosomal recessive, young onset, L-dopa-responsive parkinsonism (PARK14), suggesting a neurodegenerative condition in the nigrostriatal dopaminergic system in patients with PLA2G6 mutations. We previously observed slowly progressive motor deficits in iPLA2β-knockout (KO) mice. To clarify whether a deficiency of iPLA2β leads to the degeneration of nigrostriatal dopaminergic neurons, we analyzed the striatum of iPLA2β-KO mice. At all clinical stages, nerve terminals in the striatum were immunopositive for tyrosine hydroxylase (TH) and dopamine transporter (DAT) in wild-type (WT) control mice. In iPLA2β-KO mice, focal loss of nerve terminals positive for TH and DAT was found from 56 weeks (early clinical stage), although iPLA2β-KO mice at 56 weeks showed no significant decrease in the number of dopaminergic neurons in the substantia nigra compared with age-matched WT mice, as reported previously. At 100 weeks (late clinical stage), greater decreases in DAT immunoreactivity were observed in the striatum of iPLA2β-KO mice. Moreover, strongly TH-positive structures, presumed to be deformed axons, were observed in the neuropils of the striatum of iPLA2β-KO mice starting at 15 weeks (preclinical stage) and increased with age. These results suggest that the degeneration of dopaminergic neurons occurs mainly in the distal region of axons in iPLA2β-KO mice.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Beck
authors.affiliation: Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Koei
authors.initials: K
authors.lastname: Shinzawa
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Baba
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Sumi-Akamaru
authors.affiliation: Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.|Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019581:Neuropil / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D002118:Calcium