TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains
Identifieur interne : 000430 ( Main/Exploration ); précédent : 000429; suivant : 000431TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains
Auteurs : Silvia Zucchelli ; Marta Codrich ; Federica Marcuzzi ; Milena Pinto ; Sandra Vilotti ; Marta Biagioli ; Isidro Ferrer ; Stefano Gustincich [Italie]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-10-01.
Abstract
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.
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DOI: 10.1093/hmg/ddq290
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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.</div></front></TEI><affiliations><list><country><li>Italie</li></country></list><tree><noCountry><name sortKey="Biagioli, Marta" sort="Biagioli, Marta" uniqKey="Biagioli M" first="Marta" last="Biagioli">Marta Biagioli</name><name sortKey="Codrich, Marta" sort="Codrich, Marta" uniqKey="Codrich M" first="Marta" last="Codrich">Marta Codrich</name><name sortKey="Ferrer, Isidro" sort="Ferrer, Isidro" uniqKey="Ferrer I" first="Isidro" last="Ferrer">Isidro Ferrer</name><name sortKey="Marcuzzi, Federica" sort="Marcuzzi, Federica" uniqKey="Marcuzzi F" first="Federica" last="Marcuzzi">Federica Marcuzzi</name><name sortKey="Pinto, Milena" sort="Pinto, Milena" uniqKey="Pinto M" first="Milena" last="Pinto">Milena Pinto</name><name sortKey="Vilotti, Sandra" sort="Vilotti, Sandra" uniqKey="Vilotti S" first="Sandra" last="Vilotti">Sandra Vilotti</name><name sortKey="Zucchelli, Silvia" sort="Zucchelli, Silvia" uniqKey="Zucchelli S" first="Silvia" last="Zucchelli">Silvia Zucchelli</name></noCountry><country name="Italie"><noRegion><name sortKey="Gustincich, Stefano" sort="Gustincich, Stefano" uniqKey="Gustincich S" first="Stefano" last="Gustincich">Stefano Gustincich</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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