TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains.
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.
Zucchelli
Silvia
S
Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy.
Codrich
Marta
M
Marcuzzi
Federica
F
Pinto
Milena
M
Vilotti
Sandra
S
Biagioli
Marta
M
Ferrer
Isidro
I
Gustincich
Stefano
S
D001921:Brain / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D013379:Substrate Specificity; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D015513:Oncogene Proteins; C497604:SNCA protein, human; D048029:TNF Receptor-Associated Factor 6; D051844:alpha-Synuclein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1