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SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Mariagiovanna Malara1,2, Anne-Kathrin Lutz1, Berra Incearap1,2

  • 1Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, 89081, Ulm, Germany.

Cellular and Molecular Life Sciences : CMLS
|June 21, 2022
PubMed

Insights

SHANK3 gene mutations cause Phelan-McDermid syndrome (PMDS), impacting brain myelin. This study reveals myelin deficits in PMDS models, suggesting a key role in the disorder’s symptoms.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • SHANK3 gene mutations are linked to Phelan-McDermid syndrome (PMDS), a condition associated with autism spectrum disorders (ASDs).
  • Previous research has primarily focused on synaptic dysfunction in PMDS.

Purpose of the Study:

  • To investigate the role of SHANK3 in myelin formation and maintenance.
  • To explore the impact of SHANK3 deficiency on the central nervous system (CNS) and peripheral nervous system (PNS) myelin.

Main Methods:

  • Analysis of Shank3Δ11(-/-) mice and induced pluripotent stem cell (iPSC)-derived cerebral organoids from PMDS individuals.
  • Magnetic Resonance Imaging (MRI) to assess brain structure.
  • Western blotting to quantify myelin protein levels.
  • Electron microscopy for ultrastructural analysis of myelin sheaths.

Main Results:

  • SHANK3 is expressed in myelinating cells (oligodendrocytes and Schwann cells).
  • Shank3Δ11(-/-) mice exhibited reduced corpus callosum volume, altered myelin protein levels (decreased in CNS, increased in PNS), and changes in node/paranode lengths.
  • PMDS organoids showed delayed maturation and altered numbers of myelinating cells.

Conclusions:

  • SHANK3 deficiency significantly impairs myelin development and integrity in both the CNS and PNS.
  • Myelin dysfunction is a key pathological feature of PMDS, contributing to the syndrome's clinical manifestations alongside synaptic deregulation.
Keywords:
ASDMyelinSHANK3hiPSCs

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