Hexokinases link DJ-1 to the PINK1/parkin pathway

David N. Hauser, Adamantios Mamais, Melissa M. Conti, Christopher T. Primiani, Ravindran Kumaran, Allissa A. Dillman, Rebekah G. Langston, Alexandra Beilina, Joseph H. Garcia, Alberto Diaz-Ruiz, Michel Bernier, Fabienne Fiesel, Xu Hou, Wolfdieter Springer, Yan Li, Rafael De Cabo, Mark R. Cookson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. Methods: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved. Results: We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. Conclusion: Hexokinases are an important link between three major genetic causes of early onset Parkinson's disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.

Original languageEnglish (US)
Article number212
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Sep 29 2017

Fingerprint

Hexokinase
Parkinson Disease
Mitochondria
Brain
PTEN Phosphohydrolase
Cytosol
Cultured Cells
Rodentia
Phosphotransferases
RNA
Glucose
Food
Peptides
Proteins

Keywords

  • AKT
  • DJ-1
  • Hexokinase
  • Metabolomics
  • Mitophagy
  • Parkin
  • Parkinson's disease
  • PINK1
  • Proteomics
  • RNA-Seq
  • Systems biology

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Hauser, D. N., Mamais, A., Conti, M. M., Primiani, C. T., Kumaran, R., Dillman, A. A., ... Cookson, M. R. (2017). Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular Neurodegeneration, 12(1), [212]. https://doi.org/10.1186/s13024-017-0212-x

Hexokinases link DJ-1 to the PINK1/parkin pathway. / Hauser, David N.; Mamais, Adamantios; Conti, Melissa M.; Primiani, Christopher T.; Kumaran, Ravindran; Dillman, Allissa A.; Langston, Rebekah G.; Beilina, Alexandra; Garcia, Joseph H.; Diaz-Ruiz, Alberto; Bernier, Michel; Fiesel, Fabienne; Hou, Xu; Springer, Wolfdieter; Li, Yan; De Cabo, Rafael; Cookson, Mark R.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 212, 29.09.2017.

Research output: Contribution to journalArticle

Hauser, DN, Mamais, A, Conti, MM, Primiani, CT, Kumaran, R, Dillman, AA, Langston, RG, Beilina, A, Garcia, JH, Diaz-Ruiz, A, Bernier, M, Fiesel, F, Hou, X, Springer, W, Li, Y, De Cabo, R & Cookson, MR 2017, 'Hexokinases link DJ-1 to the PINK1/parkin pathway', Molecular Neurodegeneration, vol. 12, no. 1, 212. https://doi.org/10.1186/s13024-017-0212-x
Hauser DN, Mamais A, Conti MM, Primiani CT, Kumaran R, Dillman AA et al. Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular Neurodegeneration. 2017 Sep 29;12(1). 212. https://doi.org/10.1186/s13024-017-0212-x
Hauser, David N. ; Mamais, Adamantios ; Conti, Melissa M. ; Primiani, Christopher T. ; Kumaran, Ravindran ; Dillman, Allissa A. ; Langston, Rebekah G. ; Beilina, Alexandra ; Garcia, Joseph H. ; Diaz-Ruiz, Alberto ; Bernier, Michel ; Fiesel, Fabienne ; Hou, Xu ; Springer, Wolfdieter ; Li, Yan ; De Cabo, Rafael ; Cookson, Mark R. / Hexokinases link DJ-1 to the PINK1/parkin pathway. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1.
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AU - Garcia, Joseph H.

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AU - Bernier, Michel

AU - Fiesel, Fabienne

AU - Hou, Xu

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AU - Li, Yan

AU - De Cabo, Rafael

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N2 - Background: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. Methods: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved. Results: We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. Conclusion: Hexokinases are an important link between three major genetic causes of early onset Parkinson's disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.

AB - Background: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. Methods: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved. Results: We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. Conclusion: Hexokinases are an important link between three major genetic causes of early onset Parkinson's disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.

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