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TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains.
Hum Mol Genet. 2010 Oct 01; 19(19):3759-70.HM

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.

Authors+Show Affiliations

Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20634198

Citation

Zucchelli, Silvia, et al. "TRAF6 Promotes Atypical Ubiquitination of Mutant DJ-1 and Alpha-synuclein and Is Localized to Lewy Bodies in Sporadic Parkinson's Disease Brains." Human Molecular Genetics, vol. 19, no. 19, 2010, pp. 3759-70.
Zucchelli S, Codrich M, Marcuzzi F, et al. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Hum Mol Genet. 2010;19(19):3759-70.
Zucchelli, S., Codrich, M., Marcuzzi, F., Pinto, M., Vilotti, S., Biagioli, M., Ferrer, I., & Gustincich, S. (2010). TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. Human Molecular Genetics, 19(19), 3759-70. https://doi.org/10.1093/hmg/ddq290
Zucchelli S, et al. TRAF6 Promotes Atypical Ubiquitination of Mutant DJ-1 and Alpha-synuclein and Is Localized to Lewy Bodies in Sporadic Parkinson's Disease Brains. Hum Mol Genet. 2010 Oct 1;19(19):3759-70. PubMed PMID: 20634198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains. AU - Zucchelli,Silvia, AU - Codrich,Marta, AU - Marcuzzi,Federica, AU - Pinto,Milena, AU - Vilotti,Sandra, AU - Biagioli,Marta, AU - Ferrer,Isidro, AU - Gustincich,Stefano, Y1 - 2010/07/14/ PY - 2010/7/17/entrez PY - 2010/7/17/pubmed PY - 2011/1/5/medline SP - 3759 EP - 70 JF - Human molecular genetics JO - Hum Mol Genet VL - 19 IS - 19 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/20634198/TRAF6_promotes_atypical_ubiquitination_of_mutant_DJ_1_and_alpha_synuclein_and_is_localized_to_Lewy_bodies_in_sporadic_Parkinson's_disease_brains_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddq290 DB - PRIME DP - Unbound Medicine ER -