Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson's and other conformational diseases?
Most, if not all, neurodegenerative diseases are marked by the presence of ubiquitin-positive protein inclusions. How proteins within these inclusion bodies escape proteasomal degradation despite being enriched with ubiquitin remains a conundrum. Current evidence suggests a relationship between proteasomal impairment and inclusion formation, a persuasive explanation for the inability of the cell to remove ubiquitinated protein aggregates. Alternatively, the formation of ubiquitin-enriched inclusion may be uncoupled from the proteasome. Supporting this, we recently uncovered a novel, proteasomal-independent, catalytic activity for the Parkinson disease (PD)-linked ubiquitin ligase, parkin, that significantly enhances the formation of Lewy body (LB)-like inclusions generated in cultured cells by the co-expression of alpha-synuclein and synphilin-1. This unique activity of parkin mediates a non-classical, lysine (K) 63-linked ubiquitin multichain assembly on synphilin-1 that is distinct from the classical, degradation-associated, K48-linked ubiquitination. Interestingly, two other PD-linked gene products, alpha-synuclein and UCHL1, have recently also been associated with K63-linked ubiquitination. Inclusive of parkin, there are therefore now three PD-related gene products that are known to potentiate K63-linked ubiquitination, thus signalling an important functional relationship between this unique mode of ubiquitin tagging and PD pathogenesis. Mechanistically, the involvement of a "non-degradative" mode of ubiquitination in protein inclusion formation is an attractive explanation for how proteins are seemingly stabilized within inclusions.
Lim
Kah-Leong
KL
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Dawson
Valina L
VL
Dawson
Ted M
TM
D000818:Animals; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008954:Models, Biological; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D009088:Mucoproteins; D025801:Ubiquitin; C010393:lysin, gastropoda; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex