Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism

Biochemical and Biophysical Research Communications
Hirohide AsaiSatoshi Ueno

Abstract

Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP). We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene. Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3,4). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF(hSel-10) ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival. Collectively, we propose that naturally- and experimentally-induced exon skipping at least part...Continue Reading

References

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Citations

Mar 1, 2014·The Biochemical Journal·Donald E SprattGary S Shaw
Jun 12, 2013·Parkinsonism & Related Disorders·Ikuko OgawaSusumu Kusunoki
May 27, 2020·Journal of Human Genetics·Makito HiranoTatsushi Toda
Oct 7, 2020·International Journal of Molecular Sciences·Dunhui LiSteve D Wilton
May 22, 2021·Translational Neurodegeneration·Dunhui LiMay Thandar Aung-Htut

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