TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains

• Published in: Human molecular genetics 2010-10, Vol.19 (19), p.3759-3770
• Main Authors: Zucchelli, Silvia, Codrich, Marta, Marcuzzi, Federica, Pinto, Milena, Vilotti, Sandra, Biagioli, Marta, Ferrer, Isidro, Gustincich, Stefano
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Lewy Bodies - metabolism; Lewy Bodies - pathology; Medical sciences; Molecular and cellular biology; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Neurology; Oncogene Proteins - chemistry; Oncogene Proteins - metabolism; Parkinson Disease - metabolism; Parkinson Disease - pathology; Protein Binding; Protein Deglycase DJ-1; Protein Folding; Protein Structure, Quaternary; Protein Transport; Substrate Specificity; TNF Receptor-Associated Factor 6 - metabolism; Ubiquitination
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq290

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.