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

Neurobiology of Disease

Gergely Kustos¹  Róbert Kiss¹  Yanyan Zhao²  Manuela Kárpáti²  Judith Mihály²  Caroline H. Williams-Gray³  Balázs Herberth⁴  Zoltán Varga⁴  Wei-Li Kuan⁵  Gergely Tóth⁵  Franklin Aigbirhio⁶  Roger A. Barker⁷  Jean-Christophe Rochet⁷  Éva Moravcsik⁸  Anna Mikes⁸  Tímea Imre⁸  Balázs Fórizs⁸  Katalin Solti⁸ 

[1] Cantabio Pharmaceuticals, Palo Alto, CA, USA;Cantabio Pharmaceuticals, Palo Alto, CA, USA;Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana, USA;Institute of Materials and Environmental Chemistry Research Centre for Natural Sciences, Budapest, Hungary;John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK;MS Metabolomic Research Laboratory, Institute of Organic Chemistry, Research Center for Natural Sciences, Budapest, Hungary;Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK;TTK-NAP B - Drug Discovery Research Group – Neurodegenerative Diseases, Institute of Organic Chemistry, Research Center for Natural Sciences, Budapest, Hungary;

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

DOI  :  

来源: DOAJ

【 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 β-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.

【 授权许可】

Unknown