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.
Highlights
Phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) murine model[16], and addition of exogenous S1P to 1-methyl-4-phenylpyridinium (MPP+)-treated dopaminergic neuron cultures was found to exert a neuroprotective effect[16,17,18]
These data suggest that disruption of Plpp[3] during embryonic central nervous system (CNS) development does not cause ventral midbrain DA neuron loss or locomotor impairments consistent with PD, but results in dopaminergic transmission deficits that might contribute to the pathology under specific contexts
Genetic studies have nominated a set of candidate genes for the PARK10 locus[7,8,38,39,40], some of these findings have been controversial[41,42,43], and until now, further characterisation of these genes in the context of PD had been limited to expression analyses[9,44]
Summary
Phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD murine model[16], and addition of exogenous S1P to 1-methyl-4-phenylpyridinium (MPP+)-treated dopaminergic neuron cultures was found to exert a neuroprotective effect[16,17,18]. These observations suggest that dysregulation of S1P metabolism could play a role in PD pathogenesis. Potassium-evoked dopamine (DA) overflow in the striatum is markedly reduced in mice lacking PLPP3 These data suggest that disruption of Plpp[3] during embryonic central nervous system (CNS) development does not cause ventral midbrain DA neuron loss or locomotor impairments consistent with PD, but results in dopaminergic transmission deficits that might contribute to the pathology under specific contexts
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