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Amyotrophic lateral sclerosis (ALS) is a progressive neurode-generative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together. Amyotrophic lateral sclerosis (ALS) is a progressive neurode-generative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together. Amyotrophic lateral sclerosis (ALS) 3The abbreviations used are: ALS, amyotrophic lateral sclerosis; fALS, familial ALS; SOD1, copper-zinc superoxide dismutase; WT, wild-type; UBA, ubiquitin-association domain; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; FBS, fetal bovine serum; DAPI, 4′,6-diamidino-2-phenylindole; HA, hemagglutinin; GST, glutathione S-transferase; RIPA, radioimmune precipitation assay buffer. is a progressive neurodegenerative disorder leading to the selective death of motor neurons (1Bruijn L.I. Miller T.M. Cleveland D.W. Annu. Rev. Neurosci. 2004; 27: 723-749Crossref PubMed Scopus (1202) Google Scholar, 2Cleveland D.W. Rothstein J.D. Nat. Rev. Neurosci. 2001; 2: 806-819Crossref PubMed Scopus (1188) Google Scholar). The majority of cases are sporadic, but about 10% of all cases are familial (fALS). In ∼20% of familial cases, a mutant allele of the copper-zinc superoxide dismutase (SOD1) enzyme has been identified (3Deng H.X. Hentati A. Tainer J.A. 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However, the role of p62 in mutant SOD1-mediated fALS is In the of p62 aggregate formation or the of the accumulation of p62 in to ALS are In the the p62 protein in the G93A SOD1 mouse of fALS M.E. H. J. Hentati A. Deng H.X. P. Siddique T. Science. PubMed Scopus Google and the role of p62 in fALS mutant SOD1 aggregate formation in NSC34 cells mouse motor K. T. S. J.P. PubMed Scopus Google Scholar, K. F. A. H. Cell 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We found that the p62 was in the spinal of G93A SOD1 and progressively accumulated the of the In p62 was found in the protein aggregates in the G93A In the of p62 was and aggregates were in wild-type SOD1. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1, a role p62 in the wild-type and mutant SOD1. of p62 with SOD1 showed that aggregate formation of the SOD1 mutants and G93A was significantly enhanced by p62 WT SOD1 did not form aggregates. Deletion of the ubiquitin-association (UBA) domain of p62 decreased of mutant SOD1 but did not completely inhibit it. Further protein interaction showed that the truncated p62 the UBA domain with mutant SOD1 as the p62, that the UBA domain is not to the the p62 plays role in the formation of protein aggregates in familial WT and G93A mutant SOD1 were by of The were and M.E. H. J. Hentati A. Deng H.X. P. Siddique T. Science. PubMed Scopus Google and and as the of were identified to Gurney M.E. J. PubMed Scopus Google Scholar). G93A SOD1 were and WT SOD1 were used as were with of and with phosphate-buffered spinal and other were were by the of SOD1 was F. H. 2006; PubMed Scopus Google Scholar). The was the by the with the the and the of the The SOD1 were by SOD1 to the and of The p62 was The was by the p62 that was the and of the The p62 the UBA domain was also with in a A cells was by the of with the of The p62 and were the the The of all was by Cell and Cell cells were under in 10% fetal bovine 100 and 100 K. T. S. J.P. PubMed Scopus Google Scholar, K. F. A. H. 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As in did not form aggregates aggregates whether WT or mutant SOD1 was co-expressed of cells aggregates was co-expressed with WT SOD1 or the However, it is that WT SOD1 did not form aggregates the co-expressed p62 We the role of the UBA domain of p62 in aggregate The UBA domain has been to the of p62 to J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, B. R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). When of the p62, was co-expressed with the of cells forming aggregates decreased to 10% G93A SOD1, the of cells forming aggregates decreased to The results showed that the UBA significantly to the aggregation of mutant SOD1, that the UBA domain likely plays a role in mutant SOD1 However, with the of the of cells forming aggregates was also in G93A but the was The of UBA in the role of the UBA domain in mutant experiments and and SOD1. 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The appearance and accumulation of intracellular protein inclusions in affected motor neurons is a hallmark of The p62 protein has been found in or protein inclusions in a of neurodegenerative such as T. J. 2005; PubMed Scopus Google Scholar), K. T. T. K. S. T. T. K. Brain 2004; PubMed Scopus Google Scholar), and G. T. A. H. M. A. H. T. J. Cell Biol. 2005; 171: PubMed Scopus Google Scholar, U. Kim K. H. M. K. F. J. 2004; PubMed Scopus Google Scholar). p62 was in protein aggregates in ALS with T. K. K. Ohama E. 2004; PubMed Scopus Google Scholar), in inclusions in the motor of with ALS caused by mutations in R. G. J. P.J. 2006; PubMed Scopus Google and in other ALS cases M. M. H. B. K. J. Neurol. Sci. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). study is to whether and how p62 to mutant SOD1 aggregation and ALS and results and that p62 accumulated in parallel with the of polyubiquitinated proteins in the spinal and of G93A SOD1 the Immunostaining showed the of p62 with the and protein aggregates in affected cells in G93A The results show that p62 accumulated in protein aggregates in G93A the disease that p62 in the mutant SOD1-mediated ALS The p62 in the spinal of WT and G93A were measured by in p62 were found WT and G93A in the not The increase of p62 in the G93A not the accumulation of p62 the protein all is likely that the p62 decreased of the and in the of p62 to misfolded and polyubiquitinated proteins a more the accumulation of p62 in protein aggregates. experiments NSC34 cells showed that p62 interacted selectively with SOD1 mutants, but not with WT SOD1. of the cells with the caused increase in the of p62 with SOD1 mutants, that p62 selectively interacted with a of mutant SOD1 molecules The also caused the accumulation of polyubiquitinated SOD1 In the of the polyubiquitinated proteins in G93A SOD1 mouse spinal were significantly in the WT SOD1 In of p62 was the G93A SOD1 ubiquitin has also been that p62 to polyubiquitinated proteins J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, B. R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). to the interaction mutant SOD1 and However, deletion of the UBA domain of p62 did not the interaction p62 and mutant SOD1 that the the UBA domain and the is not to the SOD1 is likely that p62 the misfolded mutant SOD1 a the interaction p62 and mutant SOD1 is by a p62 interacting with mutant SOD1 and The interaction p62 and misfolded proteins is a p62 interaction and to whether p62 directly to the formation of mutant protein have the of p62 the aggregate formation by WT SOD1 and the mutants and G93A in NSC34 cells that have of The aggregate formation was in cells by the aggregation of SOD1 and p62 under a of p62 greatly enhanced the aggregate formation of the SOD1 mutants, but not WT SOD1 The show that p62 WT and mutant SOD1, and the aggregation of mutant SOD1. Deletion of the domain of p62 significantly to the formation of mutant SOD1 aggregates The that the UBA domain of p62 a to the formation of mutant SOD1 aggregates. The interaction results and and the protein aggregation suggest that the UBA domain plays a critical role in the aggregation of mutant SOD1 it is not to the interaction p62 and mutant SOD1. The by which p62 with mutant SOD1 and protein aggregation to in has been that p62 plays a role in protein was that p62 was in cells and was with the inclusions U. Kim K. H. M. K. F. J. 2004; PubMed Scopus Google Scholar). of p62 with the formation of ubiquitin inclusions Z. M.E. Cell Neurosci. 2005; PubMed Scopus Google Scholar). has been that p62 as a polyubiquitinated proteins to the T. J. 2005; PubMed Scopus Google and that p62 with the T. Wong Biol. 2004; PubMed Scopus Google Scholar). is likely that p62 misfolded SOD1 However, the have been to in ALS M. J. K. Takahashi R. J. PubMed Scopus Google Scholar, E. S. J. 2004; PubMed Scopus Google Scholar), the accumulation of proteins that are likely the formation of aggregates Cell Biol. 2000; 10: Full Text Full Text PDF PubMed Scopus Google Scholar, R. E. PubMed Scopus Google Scholar). The results of this study also showed that p62 aggregates of of WT or mutant SOD1 The results are in with that p62 form aggregates 2005; PubMed Scopus Google Scholar), and that p62 domain T. M. H. K. A. E. G. T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The results this study also show that p62 selectively interacted with the SOD1 that p62 mutant SOD1 aggregation by and interacting with mutant SOD1. a p62 interacting with mutant SOD1 and mutant SOD1 The SOD1 mutants have been characterized as WT SOD1 with and to form in J. G. M. D. N.G. D.R. Neurobiol. Dis. 10: PubMed Scopus Google Scholar, J.S. P.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google and in F. H. 2006; PubMed Scopus Google Scholar). decreased and to the of the mutants and not of any other cellular However, the formation of large protein aggregates greatly facilitated by p62 linking mutant SOD1 of with other and with other cellular has been the formation of protein aggregates is a or a of motor neuron death. is to both The aggregation of misfolded proteins the of the affected neurons by of proteins the other large protein aggregates to neurons by with cellular by the large protein aggregates. In has been in ALS M. J. K. Takahashi R. J. PubMed Scopus Google Scholar, E. S. J. 2004; PubMed Scopus Google Scholar). is to has been that the plays role in fALS SOD1 T. K. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). has been that p62 polyubiquitinated proteins to the G. T. A. H. M. A. H. T. J. Cell Biol. 2005; 171: PubMed Scopus Google Scholar, G. T. T. 2006; 2: PubMed Scopus Google Scholar). the interaction p62 and mutant SOD1 not to the formation of mutant SOD1 but also with of other proteins by the In p62 has been to in T. PubMed Scopus (183) Google Scholar). The protein to p62 and other proteins to the of the P.A. J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), which plays role in in neuronal and C. Neurosci. Full Text Full Text PDF PubMed Scopus Google Scholar). In p62 as a P.A. J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google as as intracellular T. J. 2005; PubMed Scopus Google Scholar). whether and how the in which p62 in mutant SOD1-mediated The viability results in the presence and absence of p62 suggest that the of p62 aggregate formation of the SOD1 mutants, but did not directly increase of death under the conditions in this study. The results of this study that p62 in mutant SOD1-mediated fALS and that p62 selectively with mutant SOD1 and mutant SOD1 The by which the SOD1 interaction motor neuron to in We WT and G93A SOD1 to the in We R. the NSC34 and are with
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