DJ-1 can form β-sheet structured aggregates that co-localize with pathological amyloid deposits

NEUROBIOLOGY OF DISEASE

卷:134

Article

Solti, Katalin¹  Kuan, Wei-Li²  Forizs, Balazs^1,3  Kustos, Gergely³  Mihaly, Judith⁴  Varga, Zoltan⁴  Herberth, Balazs^1,3  Moravcsik, Eva³  Kiss, Robert¹  Karpati, Manuela³  Mikes, Anna¹  Zhao, Yanyan⁵  Imre, Timea⁶  Rochet, Jean-Christophe^7,8  Aigbirhio, Franklin⁵  Williams-Gray, Caroline H.²  Barker, Roger A.²  Toth, Gergely^1,3 

[1] Res Ctr Nat Sci, Inst Organ Chem, TTK NAP B Drug Discovery Res Grp Neurodegenerat D, Budapest, Hungary

[2] Univ Cambridge, Dept Clin Neurosci, John van Geest Ctr Brain Repair, Forvie Site,Robinson Way, Cambridge CB2 0PY, England

[3] Cantabio Pharmaceut, Palo Alto, CA USA

[4] Res Ctr Nat Sci, Inst Mat & Environm Chem, Budapest, Hungary

[5] Univ Cambridge, Dept Clin Neurosci, Wolfson Brain Imaging Ctr, Mol Imaging Chem Lab, Cambridge CB2 0QQ, England

[6] Res Ctr Nat Sci, Inst Organ Chem, MS Metabol Res Lab, Budapest, Hungary

[7] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA

[8] Purdue Univ, Purdue Inst Integrat Neurosci, W Lafayette, IN 47907 USA

关键词: DJ-1;    Parkinson's;    Alzheimer's;    Aggregation;    Amyloid;   

DOI  :  10.1016/j.nbd.2019.104629

来源: Elsevier

【 摘 要 】

The loss of native function of the DJ-1 protein has been linked to the development of Parkinson's (PD) and other neurodegenerative diseases. Here we show that DJ-1 aggregates into beta-sheet structured soluble and fibrillar aggregates in vitro under physiological conditions and that this process is promoted by the oxidation of its catalytic Cys106 residue. This aggregation resulted in the loss of its native biochemical glyoxalase function and in addition oxidized DJ-1 aggregates were observed to localize within Lewy bodies, neurofibrillary tangles and amyloid plaques in human PD and Alzheimer's (AD) patients' post-mortem brain tissue. These findings suggest that the aggregation of DJ-1 may be a critical player in the development of the pathology of PD and AD and demonstrate that loss of DJ-1 function can happen through DJ-1 aggregation. This could then contribute to AD and PD disease onset and progression.