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Exposure at the cell surface is required for gas3/PMP22 To regulate both cell death and cell spreading: implication

C Brancolini1, P Edomi, S Marzinotto

  • 1Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia, Universita' di Udine, 33100 Udine, Italy.

Molecular Biology of the Cell
|September 12, 2000
PubMed

Insights

Point mutations in the Gas3/PMP22 gene cause Charcot-Marie-Tooth type 1A disease and Dejerine-Sottas syndrome by retaining the protein intracellularly. Reduced cell surface exposure of Gas3/PMP22 impairs its function, leading to neuropathy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • Gas3/PMP22 is a tetraspan membrane protein crucial for myelinating Schwann cells.
  • Point mutations in Gas3/PMP22 cause inherited neuropathies like Charcot-Marie-Tooth type 1A disease (CMT1A) and Dejerine-Sottas syndrome (DSS).
  • Gas3/PMP22 influences apoptosis and cell spreading, with mutations impairing these functions.

Purpose of the Study:

  • To investigate the cellular localization of wild-type (WT) and mutated Gas3/PMP22.
  • To determine the role of protein trafficking and glycosylation in Gas3/PMP22 function and disease pathogenesis.
  • To elucidate the molecular mechanisms underlying CMT1A and DSS.

Main Methods:

  • Cell surface expression analysis of Gas3/PMP22 variants.
  • Endoplasmic reticulum (ER) colocalization studies.
  • Manipulation of carboxyl-terminal retrieval signals and N-glycosylation sites.
  • Assessment of apoptosis and cell spreading assays.

Main Results:

  • Wild-type Gas3/PMP22 is cell surface-exposed, while disease-associated mutants are retained in the ER.
  • Intracellular retention of Gas3/PMP22, induced by a retrieval signal, impairs cell death regulation and alters cell spreading.
  • N-glycosylation is essential for Gas3/PMP22's effect on cell spreading but not for its role in triggering cell death.

Conclusions:

  • The molecular basis of DSS and CMT1A may stem from reduced cell surface exposure of mutated Gas3/PMP22.
  • Proper localization and function of Gas3/PMP22 at the cell surface are critical for preventing peripheral neuropathies.
  • Targeting protein trafficking or enhancing cell surface expression of Gas3/PMP22 could be therapeutic strategies.

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