Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways

Mol Neurobiol. 2018 Aug;55(8):6734-6754. doi: 10.1007/s12035-017-0846-2. Epub 2018 Jan 17.


This study aimed to gain insights into the pathophysiology underlying PLA2G6-associated neurodegeneration that is implicated in three different neurological disorders, suggesting that other, unknown genetic or environmental factors might contribute to its wide phenotypic expression. To accomplish this, we downregulated the function of pla2g6 in the zebrafish nervous system, performed parkinsonism-related phenotypic characterization, and determined the effects of gene regulation upon the loss of pla2g6 function by using RNA sequencing and downstream analyses. Pla2g6 deficiency resulted in axonal degeneration, dopaminergic and motor neuron cell loss, and increased β-synuclein expression. We also observed that many of the identified, differentially expressed genes were implicated in other brain disorders, which might explain the variable phenotypic expression of pla2g6-associated disease, and found that top enriched canonical pathways included those already known or suggested to play a major role in the pathogenesis of Parkinson's disease. Our data support that pla2g6 is relevant for cranial motor development with significant implications in the pathophysiology underlying Parkinson's disease.

Keywords: Dopaminergic and motor neuron cell loss; Elevated β-synuclein expression; Impaired brain functions and pathways; Pla2g6 deficiency.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Axons / drug effects
  • Axons / metabolism
  • Axons / pathology*
  • Base Sequence
  • Body Patterning / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology*
  • Conserved Sequence
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Group VI Phospholipases A2 / deficiency*
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism
  • Humans
  • Larva / drug effects
  • Larva / genetics
  • Larva / growth & development
  • Morpholinos / pharmacology
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Nerve Degeneration / pathology*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Zebrafish / embryology
  • Zebrafish / metabolism*
  • Zebrafish Proteins / deficiency*
  • Zebrafish Proteins / genetics
  • beta-Synuclein / metabolism*


  • Morpholinos
  • RNA, Messenger
  • Zebrafish Proteins
  • beta-Synuclein
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • Pla2g6 protein, zebrafish