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Novel splice variants of the amyotrophic lateral sclerosis-associated gene VAPB expressed in human tissues

T Nachreiner1, M Esser, V Tenten

  • 1Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Biochemical and Biophysical Research Communications
|March 16, 2010
PubMed

Insights

Researchers discovered novel VAPB splice variants in the human nervous system. These variants may accumulate in neurodegenerative diseases like ALS, potentially contributing to disease pathogenesis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Vesicle-associated membrane protein-associated protein B (VAPB) is an endoplasmic reticulum protein linked to amyotrophic lateral sclerosis type 8 (ALS8).
  • The exact pathogenesis of ALS8, despite its association with VAPB mutations, remains unclear.

Purpose of the Study:

  • To identify and characterize novel splice variants of the human VAPB gene.
  • To investigate the expression and potential role of these VAPB variants in neurodegenerative disease contexts.

Main Methods:

  • Cloning of five novel human VAPB splice variants.
  • Transfection of variants into HEK293 and SH-SY5Y cells.
  • Detection of variants via immunoblotting and proteasomal inhibition.
  • Co-immunoprecipitation assays to study protein interactions.

Main Results:

  • Five novel VAPB splice variants were identified and found to be expressed at the mRNA level in the human nervous system.
  • Two variants (VAPB-2, VAPB-4,5) were detectable in transfected cells, while two others (VAPB-3, VAPB-3,4) required proteasomal inhibition for detection.
  • VAPB-2 variant co-immunoprecipitated with wild-type VAPB.
  • No splice variants were detected in human tissue lysates, suggesting rapid degradation or low expression in vivo.

Conclusions:

  • Novel VAPB splice variants exist and are expressed in the human nervous system.
  • These variants may accumulate under proteasomal inhibition conditions, common in neurodegenerative diseases.
  • Accumulation of variant VAPB proteins could play a role in the pathogenesis of diseases like ALS.

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