RING Finger Ubiquitin-Protein Isopeptide Ligase Nrdp1/FLRF Regulates Parkin Stability and Activity

Parkin is a ubiquitin-protein isopeptide ligase. It has been suggested that loss of function in parkin causes accumulation and aggregation of its substrates, leading to death of dopaminergic neurons in Parkinson disease. Using the yeast two-hybrid screen, we isolated a RING finger protein that interacted with the N terminus of parkin in a Drosophila cDNA library. Interaction between human parkin and the mammalian RING finger protein homologue Nrdp1/FLRF, a ubiquitin-protein isopeptide ligase that ubiquitinates ErbB3 and ErbB4, was validated by in vitro binding assay, co-immunoprecipitation, and immunofluorescence co-localization. Significantly, pulse-chase experiments showed that cotransfection of Nrdp1 and parkin reduced the half-life of parkin from 5 to 2.5 h. Consistent with these findings, we further observed that degradation of CDCrel-1, a parkin substrate, was facilitated by overexpression of parkin protein. However, co-transfection of Nrdp1 with parkin reversed the effects of parkin on CDCrel-1 degradation. We conclude that Nrdp1 is a parkin modifier that accelerates degradation of parkin, resulting in a reduction of parkin activity. Parkin is a ubiquitin-protein isopeptide ligase. It has been suggested that loss of function in parkin causes accumulation and aggregation of its substrates, leading to death of dopaminergic neurons in Parkinson disease. Using the yeast two-hybrid screen, we isolated a RING finger protein that interacted with the N terminus of parkin in a Drosophila cDNA library. Interaction between human parkin and the mammalian RING finger protein homologue Nrdp1/FLRF, a ubiquitin-protein isopeptide ligase that ubiquitinates ErbB3 and ErbB4, was validated by in vitro binding assay, co-immunoprecipitation, and immunofluorescence co-localization. Significantly, pulse-chase experiments showed that cotransfection of Nrdp1 and parkin reduced the half-life of parkin from 5 to 2.5 h. Consistent with these findings, we further observed that degradation of CDCrel-1, a parkin substrate, was facilitated by overexpression of parkin protein. However, co-transfection of Nrdp1 with parkin reversed the effects of parkin on CDCrel-1 degradation. We conclude that Nrdp1 is a parkin modifier that accelerates degradation of parkin, resulting in a reduction of parkin activity. Parkinson disease (PD) 1The abbreviations used are: PD, Parksinson disease; AR-JP, autosomal recessive juvenile Parkinsonism; E3, ubiquitin-protein isopeptide ligase; HA, hemagglutinin; GST, glutathione S-transferase. is the second most common neurodegenerative disorder after Alzheimer disease with ∼500,000 patients in the United States alone. PD patients experience slowness of movement, rigidity, tremor, difficulty with balance, and variable manifestation of dementia. 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A. 2002; PubMed Scopus Google Scholar). was used to Nrdp1 protein from was from with and from that were with and a In a we to and The with and showed protein a of was from the in with and between these two further between parkin and and were on and with and was with and or and a in or with The of and Nrdp1 was in bodies neuronal and Nrdp1 are were on and with and was by and primary and and or a and a of Nrdp1 and parkin was by a were by for parkin and Nrdp1 are E3 (28Shimura H. Hattori N. Kubo S. Mizuno Y. Asakawa S. Minoshima S. Shimizu N. Iwai K. Chiba T. Tanaka K. Suzuki T. Nat. Genet. 2000; 25: 302-305Crossref PubMed Scopus (1713) Google Scholar, 31Zhang Y. Gao J. Chung K.K. Huang H. Dawson V.L. Dawson T.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13354-13359Crossref PubMed Scopus (842) Google Scholar, 32Shimura H. Schlossmacher M.G. Hattori N. Frosch M.P. Trockenbacher A. Schneider R. Mizuno Y. Kosik K.S. Selkoe D.J. 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A. 2002; PubMed Scopus Google Scholar), the C terminus of Nrdp1 effects on degradation of Significantly, we also by pulse-chase that degradation of CDCrel-1 was with Nrdp1 overexpression In this of and were in or in were with and to h. was on and in a A and In the of parkin the half-life of CDCrel-1 is overexpression of parkin CDCrel-1 with a half-life of 5 h. However, CDCrel-1 was and Nrdp1 were A and that Nrdp1 CDCrel-1 parkin activity. were in was used in C and We conclude that Nrdp1 also activity on its between Nrdp1 and parkin parkin activity on were with and or A and were with for and to h. was with was on and by C and were with 12 for h. CDCrel-1 was by and experiments were and were between with and Nrdp1 at 5 for parkin and its substrates synuclein and been Ibanez P. Abbas N. C. Bohme G.A. M. J. O. Pradier L. G. C. Periquet M. F. J. M.J. S. R. A. E. M. Denefle P. J. G. Rooney Brice A. de J. Hum. Mol. Genet. 2003; 12: PubMed Scopus Google Scholar, S.M. C. A. N. G.J. M. B.L. J. 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Neuron. 2003; 37: Full Text Full Text PDF PubMed Scopus Google Scholar). that studies of parkin and its in Drosophila provide on the pathogenesis of Parkinson disease. In this we demonstrate that a Drosophila ubiquitin E3 ligase with parkin also parkin and activity. It be and to Drosophila with either Nrdp1 or of on parkin on of parkin by Nrdp1 can be by these with Drosophila for parkin, and of the most about is Nrdp1 a in the pathogenesis of Parkinson disease. We that overexpression of Nrdp1 the parkin half-life from 5 to 2.5 h. It is to that Nrdp1 activity in the of parkin resulting in accumulation of parkin substrates Although is that the Nrdp1 on chromosome R. Mol. 2001; PubMed Scopus Google Scholar) is linked to in this and the that reduction of parkin in more death of dopaminergic neurons in Drosophila with overexpression of or Y. Y. Takahashi R. B. Neuron. 2003; 37: Full Text Full Text PDF PubMed Scopus Google Scholar) a that Nrdp1 of Parkinson disease by the of parkin protein. It is also that Nrdp1 is in the pathogenesis of the disease. Parkin contains two RING and is a ubiquitin E3 ligase. Parkin ubiquitinates its substrates and degradation. It is suggested that loss of function in parkin causes accumulation and aggregation of these substrates, resulting in death of dopaminergic However, studies in with parkin that of parkin protein has effects on of its substrates, CDCrel-1, and synuclein S.M. C. A. N. G.J. M. B.L. J. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In overexpression of parkin reduced of by overexpression of synuclein and by other than by reduction of its Y. Y. Takahashi R. B. Neuron. 2003; 37: Full Text Full Text PDF PubMed Scopus Google Scholar). or Lewy bodies or Lewy neurites were observed in PD patients with parkin mutations AR-JP patients with mutations in the parkin a loss of these that degradation of its substrates, parkin other in this we that of parkin and Nrdp1 in the pathogenesis of PD by pathways including the it be to of parkin and Nrdp1 in PD and We for cDNA We W. S. for for

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