Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia

Brain. 2020 Jun 1;143(6):1746-1765. doi: 10.1093/brain/awaa139.


TOR1A/TorsinA mutations cause two incurable diseases: a recessive congenital syndrome that can be lethal, and a dominantly-inherited childhood-onset dystonia (DYT-TOR1A). TorsinA has been linked to phosphatidic acid lipid metabolism in Drosophila melanogaster. Here we evaluate the role of phosphatidic acid phosphatase (PAP) enzymes in TOR1A diseases using induced pluripotent stem cell-derived neurons from patients, and mouse models of recessive Tor1a disease. We find that Lipin PAP enzyme activity is abnormally elevated in human DYT-TOR1A dystonia patient cells and in the brains of four different Tor1a mouse models. Its severity also correlated with the dosage of Tor1a/TOR1A mutation. We assessed the role of excess Lipin activity in the neurological dysfunction of Tor1a disease mouse models by interbreeding these with Lpin1 knock-out mice. Genetic reduction of Lpin1 improved the survival of recessive Tor1a disease-model mice, alongside suppressing neurodegeneration, motor dysfunction, and nuclear membrane pathology. These data establish that TOR1A disease mutations cause abnormal phosphatidic acid metabolism, and suggest that approaches that suppress Lipin PAP enzyme activity could be therapeutically useful for TOR1A diseases.

Keywords: TOR1A; brain development; dystonia; metabolic disease; movement disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Disease Models, Animal
  • Dystonia / genetics
  • Dystonia / metabolism
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Neurons / metabolism
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Phosphatidate Phosphatase / physiology


  • Dyt1 protein, mouse
  • Molecular Chaperones
  • TOR1A protein, human
  • LPIN1 protein, human
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase