Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases.
Mutations in DJ-1 cause an autosomal recessive, early onset familial form of Parkinson disease (PD). However, little is presently known about the role of DJ-1 in the more common sporadic form of PD and in other age-related neurodegenerative diseases, such as Alzheimer disease (AD). Here we report that DJ-1 is oxidatively damaged in the brains of patients with idiopathic PD and AD. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified 10 different DJ-1 isoforms, of which the acidic isoforms (pI 5.5 and 5.7) of DJ-1 monomer and the basic isoforms (pI 8.0 and 8.4) of SDS-resistant DJ-1 dimer are selectively accumulated in PD and AD frontal cortex tissues compared with age-matched controls. Quantitative Western blot analysis shows that the total level of DJ-1 protein is significantly increased in PD and AD brains. Mass spectrometry analyses reveal that DJ-1 is not only susceptible to cysteine oxidation but also to previously unsuspected methionine oxidation. Furthermore, we show that DJ-1 protein is irreversibly oxidized by carbonylation as well as by methionine oxidation to methionine sulfone in PD and AD. Our study provides new insights into the oxidative modifications of DJ-1 and indicates association of oxidative damage to DJ-1 with sporadic PD and AD.
Choi
Joungil
J
Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Sullards
M Cameron
MC
Olzmann
James A
JA
Rees
Howard D
HD
Weintraub
Susan T
ST
Bostwick
David E
DE
Gearing
Marla
M
Levey
Allan I
AI
Chin
Lih-Shen
LS
Li
Lian
L
D019297:2,4-Dinitrophenol / Q000737:chemistry; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002244:Carbon / Q000737:chemistry; D002540:Cerebral Cortex / Q000473:pathology; D019281:Dimerization; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007526:Isoelectric Point; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry; D008875:Middle Aged; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases; D015513:Oncogene Proteins / Q000378:metabolism* / Q000502:physiology*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000737:chemistry; D000071617:Protein Deglycase DJ-1; D020033:Protein Isoforms; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors
D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D015513:Oncogene Proteins; D010455:Peptides; D020033:Protein Isoforms; D002244:Carbon; D008715:Methionine; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D019297:2,4-Dinitrophenol; D010100:Oxygen