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CADASIL mutations enhance spontaneous multimerization of NOTCH3

Christian Opherk1, Marco Duering, Nils Peters

  • 1Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

Human Molecular Genetics
|May 7, 2009
PubMed

Insights

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is linked to mutations in the NOTCH3 receptor. These mutations enhance the self-association of the NOTCH3 extracellular domain, leading to its accumulation and cell degeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the leading monogenic cause of stroke and vascular dementia.
  • Mutations causing CADASIL occur in the NOTCH3 receptor's extracellular domain (N3(ECD)), specifically affecting cysteine residues.
  • A key feature of CADASIL is the accumulation of N3(ECD) on vascular smooth muscle cells, leading to their degeneration, but the underlying mechanism is unknown.

Purpose of the Study:

  • To investigate the molecular mechanisms behind N3(ECD) accumulation in CADASIL.
  • To determine if N3(ECD) undergoes self-association and if CADASIL mutations influence this process.

Main Methods:

  • In vitro analysis of wild-type and CADASIL-mutated N3(ECD) multimerization.
  • Utilized scanning for intensely fluorescent targets (SIFT) single-molecule analysis techniques.
  • Investigated the role of disulfide bonds in N3(ECD) multimerization.

Main Results:

  • Both wild-type and CADASIL-mutated N3(ECD) spontaneously form oligomers and multimers in vitro.
  • Multimerization is mediated by disulfide bonds.
  • CADASIL mutations significantly enhance N3(ECD) multimerization compared to the wild-type receptor.

Conclusions:

  • This study provides the first experimental evidence for NOTCH3 receptor self-association.
  • CADASIL-associated mutations appear to induce a neomorphic effect, promoting N3(ECD) multimerization and contributing to disease pathogenesis.

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