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HoxB2 binds mutant SOD1 and is altered in transgenic model of ALS

Jinbin Zhai1, Hong Lin, Rafaela Canete-Soler

  • 1Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. wws435jp@mail.med.upenn.edu

Human Molecular Genetics
|August 5, 2005
PubMed

Insights

HoxB2 protein interacts with mutant superoxide dismutase 1 (SOD1) in motor neurons, potentially modulating neurotoxicity in familial amyotrophic lateral sclerosis (ALS). This interaction may offer new therapeutic targets for ALS.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in copper-zinc superoxide dismutase (SOD1) are a significant cause of familial amyotrophic lateral sclerosis (ALS).
  • The exact mechanisms underlying SOD1-related ALS pathogenesis, particularly the toxic gain of function, are not fully understood.

Purpose of the Study:

  • To identify proteins that interact with G93A mutant SOD1.
  • To investigate the role of the identified interaction in the context of mutant SOD1-mediated neurotoxicity in ALS.

Main Methods:

  • Yeast two-hybrid screening to identify interacting proteins.
  • Co-immunoprecipitation and co-localization studies in neuronal cell lines and transgenic mouse models.
  • Mutagenesis to map the interaction domain.
  • Assessment of cell viability and protein insolubility.

Main Results:

  • HoxB2, a transcription factor, was identified as an interacting protein with G93A mutant SOD1.
  • HoxB2 co-precipitates and co-localizes with mutant SOD1 in neuronal cells and in vivo.
  • The interaction is mediated by HoxB2's homeodomain.
  • Overexpression of HoxB2 reduces mutant SOD1 insolubility and protects against mutant SOD1-induced cell death.
  • HoxB2 redistributes and accumulates with mutant SOD1 in motor neurons of G93A transgenic mice.

Conclusions:

  • HoxB2 interacts with mutant SOD1 within motor neurons.
  • This interaction may play a role in modulating the neurotoxic effects of mutant SOD1 in ALS.
  • HoxB2 represents a potential target for therapeutic intervention in SOD1-related ALS.

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