Mitochondrial localization of the Parkinson's disease related protein DJ-1: Implications for pathogenesis

Li Zhang, Mika Shimoji, Bobby Thomas, Darren J. Moore, Seong Woon Yu, Neena I. Marupudi, Reidun Torp, Ingeborg A. Torgner, Ole P. Ottersen, Ted M. Dawson, Valina L. Dawson

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Abstract

Both homozygous (L166P, M26I, deletion) and heterozygous mutations (D149A, A104T) in the DJ-1 gene have been identified in Parkinson's disease (PD) patients. The biochemical function and subcellular localization of DJ-1 protein have not been clarified. To date the localization of DJ-1 protein has largely been described in studies over-expressing tagged DJ-1 protein in vitro. It is not known whether the subcellular localization of over-expressed DJ-1 protein is identical to that of endogenously expressed DJ-1 protein both in vitro and in vivo. To clarify the subcellular localization and function of DJ-1, we generated three highly specific antibodies to DJ-1 protein and investigated the subcellular localization of endogenous DJ-1 protein in both mouse brain tissues and human neuroblastoma cells. We have found that DJ-1 is widely distributed and is highly expressed in the brain. By cell fractionation and immunogold electron microscopy, we have identified an endogenous pool of DJ-1 in mitochondrial matrix and inter-membrane space. To further investigate whether pathogenic mutations might prevent the distribution of DJ-1 to mitochondria, we generated human neuroblastoma cells stably transfected with wild-type (WT) or mutant (M26I, L166P, A104T, D149A) DJ-1 and performed mitochondrial fractionation and confocal co-localization imaging studies. When compared with WT and other mutants, L166P mutant exhibits largely reduced protein level. However, the pathogenic mutations do not alter the distribution of DJ-1 to mitochondria. Thus, DJ-1 is an integral mitochondrial protein that may have important functions in regulating mitochondrial physiology. Our findings of DJ-1's mitochondrial localization may have important implications for understanding the pathogenesis of PD.

Original languageEnglish (US)
Pages (from-to)2063-2073
Number of pages11
JournalHuman Molecular Genetics
Volume14
Issue number14
DOIs
StatePublished - Jul 15 2005

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Neuroblastoma
Parkinson Disease
Mitochondria
Cell Fractionation
Mutation
Sequence Deletion
Mitochondrial Proteins
Brain
Mitochondrial Parkinson Disease
Protein Deglycase DJ-1
Electron Microscopy
Membranes
Antibodies
Genes
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Zhang, L., Shimoji, M., Thomas, B., Moore, D. J., Yu, S. W., Marupudi, N. I., ... Dawson, V. L. (2005). Mitochondrial localization of the Parkinson's disease related protein DJ-1: Implications for pathogenesis. Human Molecular Genetics, 14(14), 2063-2073. https://doi.org/10.1093/hmg/ddi211

Mitochondrial localization of the Parkinson's disease related protein DJ-1 : Implications for pathogenesis. / Zhang, Li; Shimoji, Mika; Thomas, Bobby; Moore, Darren J.; Yu, Seong Woon; Marupudi, Neena I.; Torp, Reidun; Torgner, Ingeborg A.; Ottersen, Ole P.; Dawson, Ted M.; Dawson, Valina L.

In: Human Molecular Genetics, Vol. 14, No. 14, 15.07.2005, p. 2063-2073.

Research output: Contribution to journalArticle

Zhang, L, Shimoji, M, Thomas, B, Moore, DJ, Yu, SW, Marupudi, NI, Torp, R, Torgner, IA, Ottersen, OP, Dawson, TM & Dawson, VL 2005, 'Mitochondrial localization of the Parkinson's disease related protein DJ-1: Implications for pathogenesis', Human Molecular Genetics, vol. 14, no. 14, pp. 2063-2073. https://doi.org/10.1093/hmg/ddi211
Zhang, Li ; Shimoji, Mika ; Thomas, Bobby ; Moore, Darren J. ; Yu, Seong Woon ; Marupudi, Neena I. ; Torp, Reidun ; Torgner, Ingeborg A. ; Ottersen, Ole P. ; Dawson, Ted M. ; Dawson, Valina L. / Mitochondrial localization of the Parkinson's disease related protein DJ-1 : Implications for pathogenesis. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 14. pp. 2063-2073.
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