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Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

T Manabe1, T Katayama, N Sato

  • 1Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.

Cell Death and Differentiation
|May 23, 2003
PubMed

Insights

Aberrant splicing of the Presenilin-2 gene (PS2V) is linked to Alzheimer's disease (AD). Hypoxia induces the high mobility group A1a protein (HMGA1a), which causes PS2V by disrupting splicing, offering a new AD mechanism.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Aberrant splicing of the Presenilin-2 (PS2) gene, producing the PS2V isoform, is a hallmark of sporadic Alzheimer's disease (AD).
  • The molecular mechanisms driving this aberrant splicing in AD remain largely unknown.

Purpose of the Study:

  • To identify the trans-acting factors responsible for hypoxia-induced PS2V generation.
  • To elucidate the role of these factors in the pathogenesis of sporadic AD.

Main Methods:

  • Hypoxia induction in human neuroblastoma cells (SK-N-SH).
  • Purification and identification of a trans-acting factor binding to PS2 exon 5.
  • Overexpression studies of identified factor and splicing factors.
  • Analysis of HMGA1a levels in brain tissue from sporadic AD patients.

Main Results:

  • PS2V splicing is induced by hypoxia in neuronal cells.
  • High mobility group A1a protein (HMGA1a) was identified as the hypoxia-inducible factor binding to PS2 exon 5.
  • HMGA1a overexpression promotes PS2V formation by interfering with U1 snRNP binding, leading to exon 5 skipping.
  • HMGA1a levels are significantly elevated in the brains of sporadic AD patients.

Conclusions:

  • HMGA1a is a key mediator of hypoxia-induced aberrant PS2 splicing.
  • HMGA1a-driven PS2V generation represents a novel molecular mechanism in sporadic Alzheimer's disease pathogenesis.
  • Targeting HMGA1a may offer a therapeutic strategy for sporadic AD.

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