TY - JOUR
T1 - Parkin-mediated lysine 63-linked polyubiquitination
T2 - A link to protein inclusions formation in Parkinson's and other conformational diseases?
AU - Lim, Kah Leong
AU - Dawson, Valina L.
AU - Dawson, Ted M.
N1 - Funding Information:
This work was supported by grants from NIH/NINDS Morris K. Udall Parkinson's Disease Research Center – NS38377, NS48206, the Lee Martin Trust, the Sylvia Nachlas Trust, the National Medical Research Council NMRC/0776/2003, Singapore (LKL). TMD is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.
PY - 2006/4
Y1 - 2006/4
N2 - 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 α-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, α-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.
AB - 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 α-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, α-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.
KW - Lewy body
KW - Lysine-63
KW - Parkin
KW - Parkinson's disease
KW - Proteasome
KW - Ubiquitin
KW - Ubiquitin proteasomal system
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U2 - 10.1016/j.neurobiolaging.2005.07.023
DO - 10.1016/j.neurobiolaging.2005.07.023
M3 - Review article
C2 - 16213628
AN - SCOPUS:33344456519
VL - 27
SP - 524
EP - 529
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 4
ER -