Phosphatase PP2A is Required for CNS Myelination via Proteasome-Dependent Regulation of Sox10 Expression

Mengjia Liu1,2, Yajie Zhang1,2, Xiao-Yu Teng3

  • 1MOE Key Laboratory of Model Animal for Disease Study, Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.

Glia
|September 11, 2025
PubMed

Insights

Loss-of-function mutations in protein phosphatase 2A (PP2A) cause hypomyelination. Inactivating PP2A in oligodendrocyte cells impairs motor coordination by reducing SOX10 levels.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Loss-of-function mutations in protein phosphatase 2A (PP2A) subunits are linked to hypomyelination and motor deficits.
  • The precise mechanisms underlying these neurological disorders remain unclear.

Purpose of the Study:

  • To investigate the role of PP2A catalytic subunit alpha (PP2Acα) in oligodendrocyte lineage cells.
  • To elucidate the molecular mechanisms connecting PP2A dysfunction to white matter abnormalities and motor impairments.

Main Methods:

  • Generation of a conditional knockout mouse model with inactivated PP2Acα specifically in oligodendrocyte lineage cells.
  • Assessment of oligodendrogenesis and motor functions, including fine motor coordination and balance.
  • Analysis of SOX10 protein levels and its regulation via proteasomal degradation.

Main Results:

  • PP2A mutant mice displayed reduced oligodendrogenesis and deficits in fine motor coordination and balance.
  • Inactivation of PP2Acα led to a proteasome-dependent down-regulation of the SOX10 transcription factor.
  • This study establishes a direct link between PP2A function in oligodendrocytes and white matter integrity.

Conclusions:

  • PP2A is crucial for proper oligodendrogenesis and motor function in the central nervous system.
  • The proteasome-mediated degradation of SOX10 is a key mechanism by which PP2A loss-of-function causes hypomyelination.
  • Findings offer insights into the pathogenesis of diseases characterized by white matter abnormalities and motor coordination defects.

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