title: Neural ablation of the PARK10 candidate Plpp3 leads to dopaminergic transmission deficits without neurodegeneration.
abstract: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, characterised by the progressive loss of midbrain dopaminergic neurons and a variety of motor symptoms. The gene coding for the phospholipid phosphatase 3, PLPP3 (formerly PPAP2B or LPP3), maps within the PARK10 locus, a region that has been linked with increased risk to late-onset PD. PLPP3 modulates the levels of a range of bioactive lipids controlling fundamental cellular processes within the central nervous system. Here we show that PLPP3 is enriched in astroglial cells of the adult murine ventral midbrain. Conditional inactivation of Plpp3 using a Nestin::Cre driver results in reduced mesencephalic levels of sphingosine-1-phosphate receptor 1 (S1P1), a well-known mediator of pro-survival responses. Yet, adult PLPP3-deficient mice exhibited no alterations in the number of dopaminergic neurons or in the basal levels of striatal extracellular dopamine (DA). Potassium-evoked DA overflow in the striatum, however, was significantly decreased in mutant mice. Locomotor evaluation revealed that, although PLPP3-deficient mice exhibit motor impairment, this is not progressive or responsive to acute L-DOPA therapy. These findings suggest that disruption of Plpp3 during early neural development leads to dopaminergic transmission deficits in the absence of nigrostriatal degeneration, and without causing an age-related locomotor decline consistent with PD.
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gómez-López
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Ana Valeria
authors.initials: AV
authors.lastname: Martínez-Silva
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Montiel
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Daniel
authors.initials: D
authors.lastname: Osorio-Gómez
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Federico
authors.initials: F
authors.lastname: Bermúdez-Rattoni
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Massieu
authors.affiliation: Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City, 04510, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Escalante-Alcalde
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D008124:Locomotion / Q000502:physiology; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049294:Phospholipid Transfer Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D049294:Phospholipid Transfer Proteins; C493428:Plscr3 protein, mouse; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D004298:Dopamine