SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2008202443> ?p ?o ?g. }

Showing items 1 to 94 of 94 with 100 items per page.

W2008202443 endingPage "19227" @default.
W2008202443 startingPage "19220" @default.
W2008202443 abstract "Huntington's disease (HD) is caused by the expansion of a glutamine repeat in the protein huntingtin. The expanded glutamine repeat is thought to mediate a gain of function by causing huntingtin to abnormally interact with other proteins. We previously identified a rat huntingtin-associated protein (HAP1) that binds to huntingtin; HAP1 binds more tightly to huntingtin with an expanded glutamine repeat than to wild type huntingtin. Identification of the human homologue of HAP1 is necessary for investigation of the potential role of HAP1 in HD pathology. Here, we report the cloning of a human HAP1 homologue (hHAP) that shares 62% identity with rat HAP1 over its entire sequence and 82% amino acid identity in the putative huntingtin-binding region. The hHAP gene encodes a 4.1-kilobase transcript and a 75-kDa protein which are specifically expressed in human brain tissues. Its expression in Huntington's disease brains is reduced in parallel with a decreased expression of huntingtin. While two isoforms of rat HAP1 are expressed at similar levels in rat brain, only a single major form of hHAP is found in primate brains. In vitro binding, immunoprecipitation, and coexpression studies confirm the interaction of hHAP with huntingtin. The in vitro binding of hHAP to huntingtin is enhanced by lengthening the glutamine repeat. Despite similar binding properties of rat HAP1 and hHAP, differences in the sequences and expression of hHAP may contribute to a specific role for its interaction with huntingtin in humans. Huntington's disease (HD) is caused by the expansion of a glutamine repeat in the protein huntingtin. The expanded glutamine repeat is thought to mediate a gain of function by causing huntingtin to abnormally interact with other proteins. We previously identified a rat huntingtin-associated protein (HAP1) that binds to huntingtin; HAP1 binds more tightly to huntingtin with an expanded glutamine repeat than to wild type huntingtin. Identification of the human homologue of HAP1 is necessary for investigation of the potential role of HAP1 in HD pathology. Here, we report the cloning of a human HAP1 homologue (hHAP) that shares 62% identity with rat HAP1 over its entire sequence and 82% amino acid identity in the putative huntingtin-binding region. The hHAP gene encodes a 4.1-kilobase transcript and a 75-kDa protein which are specifically expressed in human brain tissues. Its expression in Huntington's disease brains is reduced in parallel with a decreased expression of huntingtin. While two isoforms of rat HAP1 are expressed at similar levels in rat brain, only a single major form of hHAP is found in primate brains. In vitro binding, immunoprecipitation, and coexpression studies confirm the interaction of hHAP with huntingtin. The in vitro binding of hHAP to huntingtin is enhanced by lengthening the glutamine repeat. Despite similar binding properties of rat HAP1 and hHAP, differences in the sequences and expression of hHAP may contribute to a specific role for its interaction with huntingtin in humans. Huntingtin is the protein product of the gene for Huntington's disease (HD). 1The abbreviations used are: HD, Huntington's disease; HAP1, huntingtin-associated protein; hHAP, human huntingtin-associated protein; GST, glutathioneS-transferase; DRPLA, dentatorubral and pallidoluysian atrophy; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; PBS, phosphate-buffered saline; RT, reverse transcriptase; PAGE, polyacrylamide gel electrophoresis; kb, kilobase(s). 1The abbreviations used are: HD, Huntington's disease; HAP1, huntingtin-associated protein; hHAP, human huntingtin-associated protein; GST, glutathioneS-transferase; DRPLA, dentatorubral and pallidoluysian atrophy; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; PBS, phosphate-buffered saline; RT, reverse transcriptase; PAGE, polyacrylamide gel electrophoresis; kb, kilobase(s). The N terminus of human huntingtin contains a glutamine stretch encoded by a CAG repeat (1HD Collaborative Research Group Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (6956) Google Scholar). Expansion of the CAG/glutamine repeat (>37 units) causes HD (1HD Collaborative Research Group Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (6956) Google Scholar) and the length of the CAG repeat is inversely correlated with the age of onset of HD (2Duyao M.P. Taylor S.A. Buckler A.J. Ambrose C.M. Lin C. Groot N. Church D. Barnes G. Wasmuth J.J. Housman D.E. et al.Hum. Mol. Genet. 1993; 2: 673-676Crossref PubMed Scopus (20) Google Scholar, 3Andrew S.E. Goldberg Y.P. Kremer B. Telenius H. Theilmann J. Adam S. Starr E. Squitieri F. Lin B. Kalchman M.A. et al.Nat. Genet. 1993; 4: 398-403Crossref PubMed Scopus (867) Google Scholar, 4Stine O.C. Pleasant N. Franz M.L. Abbott M.H. Folstein S.E. Ross C.A. Hum. Mol. Genet. 1993; 2: 1547-1549Crossref PubMed Scopus (212) Google Scholar).Although the genetic basis of HD has been identified, its pathogenesis remains unclear. The widespread expression of huntingtin does not explain the selective neuropathology of HD, which is characterized by massive neuronal loss specifically in the basal ganglia (5Martin J.B. Gusella J.F. N. Engl. J. Med. 1986; 315: 1267-1276Crossref PubMed Scopus (15) Google Scholar, 6Vonsattel J.P. Myers R.H. Stevens T.J. Ferrante R.J. Bird E.D. Richardson Jr., E.P. J. Neuropathol. Exp. Neurol. 1985; 44: 559-577Crossref PubMed Scopus (2054) Google Scholar, 7Ferrante R.J. Kowall N.W. Beal M.F. Richardson Jr., E.P. Bird E.D. Martin J.B. Science. 1985; 230: 561-563Crossref PubMed Scopus (670) Google Scholar). Since mice that lack huntingtin or express reduced levels of huntingtin display aberrant brain development and perinatal lethality (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar), huntingtin is thought to be important for neurogenesis. However, loss of huntingtin activity is unlikely the cause of HD because heterozygous HD inactivation by translocation in man (9Ambrose C.M. Duyao M.P. Barnes G. Bates G.P. Lin C.S. Srinidhi J. Baxendale S. Hummerich H. Lehrach H. Altherr M. et al.Somat. Cell Mol. Genet. 1994; 20: 27-38Crossref PubMed Scopus (225) Google Scholar) or by targeted mutagenesis of the mouse HD gene (10Duyao M.P. Auerbach A.B. Ryan A. Persichetti F. Barnes G.T. McNeil S.M. Ge P. Vonsattel J.P. Gusella J.F. Joyner A.L. et al.Science. 1995; 269: 407-410Crossref PubMed Scopus (565) Google Scholar, 11Nasir J. Floresco S.B. O'Kusky J.R. Diewert V.M. Richman J.M. Zeisler J. Borowski A. Marth J.D. Phillips A.G. Hayden M.R. Cell. 1995; 81: 811-823Abstract Full Text PDF PubMed Scopus (667) Google Scholar) does not cause any HD phenotype. A gain of function model for the disease is thus widely accepted. It has been proposed that the expanded glutamine repeat may induce an abnormal interaction between the mutant protein and other cellular proteins (12Albin R.L. Tagle D.A. Trends Neurosci. 1995; 18: 11-14Abstract Full Text PDF PubMed Scopus (132) Google Scholar, 13Ross C.A. Neuron. 1995; 15: 493-496Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 14MacDonald M.E. Gusella J.F. Curr. Opin. Neurobiol. 1996; 6: 638-643Crossref PubMed Scopus (86) Google Scholar). Consistent with this idea, studies to date have shown that huntingtin interacts with several proteins including HAP1 (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar), glyceraldehyde phosphate dehydrogenase (GAPDH) (16Burke J.R. Enghild J.J. Martin M.E. Jou Y.S. Myers R.M. Roses A.D. Vance J.M. Strittmatter W.J. Nat. Med. 1996; 2: 347-350Crossref PubMed Scopus (403) Google Scholar), an unidentified calmodulin-associated protein (17Bao J. Sharp A.H. Wagster M.V. Becher M. Schilling G. Ross C.A. Dawson V.L. Dawson T.M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5037-5042Crossref PubMed Scopus (131) Google Scholar), and a protein homologous to the yeast cytoskeleton-associated protein Sla2p (HIP1) (18Kalchman M.A. Koide H.B. McCutcheon K. Graham R.K. Nichol K. Nishiyama K. Kazemi-Esfarjani P. Lynn F.C. Wellington C. Metzler M. Goldberg Y.P. Kanazawa I. Gietz R.D. Hayden M.R. Nat. Genet. 1997; 16: 44-53Crossref PubMed Scopus (317) Google Scholar, 19Wanker E.E. Rovira C. Scherzinger E. Hasenbank R. Walter S. Tait D. Colicelli J. Lehrach H. Hum. Mol. Genet. 1997; 6: 487-495Crossref PubMed Scopus (289) Google Scholar). These huntingtin-associated proteins are likely involved in HD pathology because their interactions with huntingtin are affected by an expanded glutamine repeat.HAP1 was first identified in rat brain and was found to bind to the N-terminal region of human huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar). It binds more tightly to mutant huntingtin than to normal huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar). Furthermore, rat HAP1 is specifically expressed in neurons (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar), making it a good candidate to be involved in the neuropathology of HD. Recent studies also show that rat HAP1 associates with a number of intracellular organelles (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar, 21Gutekunst C.A. Li S.H. Yi H. Ferrante R.J. Li X.J. Hersch S.M. Soc. Neurosci. Abstr. 1997; 23: 1911Google Scholar, 22Martin E.J. Kim M. Velier J. Lee H.S. Chase K. Won L.A. Bhide P.G. Heller A. Aronin N. DiFiglia M. Soc. Neurosci. Abstr. 1997; 23: 1910Google Scholar), moves with huntingtin in nerve fibers (23Block-Galarza J. Chase K.O. Sapp E. Vaughn K.T. Vallee R.B. DiFiglia M. Aronin N. Neuroreport. 1997; 8: 2247-2251Crossref PubMed Scopus (120) Google Scholar), and interacts with dynactin P150Glued (24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar, 25Engelender S. Sharp A.H. Colomer V. Tokito M.K. Lanahan A. Worley P. Holzbaur E.L.F. Ross C.A. Hum. Mol. Genet. 1997; 6: 2205-2212Crossref PubMed Scopus (275) Google Scholar) which participates in dynein-mediated retrograde transport. It remains to be shown whether human brain also contains a HAP1 homologue with similar binding properties. Since mice with normal levels of mutant huntingtin do not display any abnormal phenotype (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar), specific properties of the proteins which associate with human huntingtin may account for the HD phenotype that occurs in man. Therefore, it will be interesting to identify human proteins that associate with huntingtin.In this study, we isolated a human HAP1 homologue (hHAP) by molecular cloning. hHAP shares 62% amino acid identity with rat HAP1-A. Although its binding to huntingtin is comparable to that of rat HAP1, hHAP only has a single major form expressed in primate brains, in contrast to two isoforms of HAP1 in rat brain. The different sequences and expression of hHAP could contribute to a specific role in the interaction of hHAP and huntingtin in human brain. Identification of the human HAP1 homologue will facilitate the study of the relevance of the interaction between HAP1 and huntingtin in the pathology of HD.DISCUSSIONSeveral lines of evidence in the present study demonstrate that hHAP is a human counterpart of rat HAP1. First, the sequence of hHAP shows a high degree of homology to that of rat HAP1. Second, like rat HAP1 (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar), primate HAP1 is enriched in monkey and human brains. In addition, hHAP appears to be expressed with huntingtin in the neurons that are vulnerable in HD. Third, in vitro binding, immunoprecipitation, and coexpression studies consistently show that hHAP specifically interacts with huntingtin, and its in vitro binding seems to be enhanced by an expanded glutamine repeat. Rat HAP1 has been also found to bind more tightly to huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar). The similarity of hHAP and rat HAP1 in their sequences and binding to huntingtin suggests that hHAP and rat HAP1 bind to huntingtin in the same manner.There are also differences between hHAP and rat HAP1. The amino acid sequences of hHAP display a number of insertions or deletions when compared with the sequences of rat HAP1. Unlike huntingtin which is highly conserved between humans and rodents (91% amino acid identity), hHAP and rat HAP1 share 62% amino acid identity overall. However, amino acids in the huntingtin-binding regions of both proteins are well conserved (82% identity), suggesting that their binding properties are similar while other functional aspects may not be identical. In addition, unlike rat HAP1 which is expressed as two isoforms (HAP1-A and HAP1-B), hHAP only displays a single major form in primate brains. The expression pattern of hHAP in transfected cells is also different from that of rat HAP1-A. These differences may reflect unique properties of hHAP that could confer a specific role of the interaction of HAP1 and huntingtin in human brain.Several hHAP cDNA variants were found during cDNA screening. Most of them have insertions or deletions after the putative huntingtin-binding region. This may explain why no one has succeeded in isolating hHAP using yeast two-hybrid screening. However, the hHAP amino acid sequence presented in Fig. 1 is likely to represent the major protein product of the hHAP gene. This is because the cDNA probe and the antibody to the middle region of cloned hHAP consistently detect a major band on Northern and Western blots, respectively. Also, the mass of transfected hHAP is the same as that of native hHAP on Western blots. Several other weak bands are also seen. These weak bands could represent alternatively spliced products or other homologues of hHAP. Whether other hHAP cDNA variants are also expressed remains to be studied using antibodies specifically to their encoding amino acids.Identification of hHAP further suggests a potential role of HAP1 in the pathology of HD. First, the parallel reduction in the expression of huntingtin and hHAP in the HD brains suggests that both proteins are expressed in the same neurons that are vulnerable in HD. However, the expression of hHAP is not restricted to the brain regions that can be affected in HD. The selective neurodegeneration in HD may also be associated with heterogeneous expression of huntingtin in the striatum (32Ferrante R.J. Gutekunst C.A. Persichetti F. McNeil S.M. Kowall N.W. Gusella J.F. MacDonald M.E. Beal M.F. Hersch S.M. J. Neurosci. 1997; 17: 3052-3063Crossref PubMed Google Scholar) and/or other specific neuronal factors. Second, like rat HAP1, hHAP binds to the N-terminal region of huntingtin in vitro. Proteins that bind to the N-terminal region of huntingtin are especially interesting because the N-terminal fragment of huntingtin (amino acids 1–67) with an additional 150 glutamines has been found to cause neurological disorders in transgenic mice (31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar). We observed that the binding of the N-terminal huntingtin (amino acids 1–230) with the glutamine repeat (23Q, 44Q, or 73Q) to GST-hHAP is increased by lengthening the repeat. Although the increase is not dramatic in vitro, it could contribute to cumulative effects of huntingtin mutation or late onset of pathophysiology if it also occurs in vivo. The interaction of hHAP and huntingtin is also supported by their co-localization in hHAP immunoreactive inclusions in transfected cells. Their co-localization is specific because DRPLA, another glutamine repeat protein, does not co-localize with hHAP on these distinct structures. Rat HAP1 has been found to associate with similar cytoplasmic structures in the rat brain. 2C. A. Gutekunst, S-H. Li, X-J. Li, and S. M. Hersch, unpublished observations. Whether human brain also contains hHAP immunoreactive cytoplasmic inclusions remains to be studied.Unique components or specific properties of human huntingtin complexes may account for the neuropathology of HD in man. This is suggested by recent findings that transgenic mice expressing mutant human huntingtin do not display the graded loss of neurons in brain (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar, 31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar) that is the hallmark of human HD disease (5Martin J.B. Gusella J.F. N. Engl. J. Med. 1986; 315: 1267-1276Crossref PubMed Scopus (15) Google Scholar, 6Vonsattel J.P. Myers R.H. Stevens T.J. Ferrante R.J. Bird E.D. Richardson Jr., E.P. J. Neuropathol. Exp. Neurol. 1985; 44: 559-577Crossref PubMed Scopus (2054) Google Scholar, 7Ferrante R.J. Kowall N.W. Beal M.F. Richardson Jr., E.P. Bird E.D. Martin J.B. Science. 1985; 230: 561-563Crossref PubMed Scopus (670) Google Scholar). It is possible that expansion of the huntingtin glutamine repeat may alter specific properties of human huntingtin-associated proteins, such as hHAP, and this alteration could contribute to the neuropathology of HD in man. Identification of hHAP will promote the study of the potential role of the interaction of HAP1 and huntingtin in the pathology of HD. hHAP may also be involved in the normal function of human huntingtin. This is suggested by recent studies showing that rat HAP1 associates with dynactin P150Glued (24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar, 25Engelender S. Sharp A.H. Colomer V. Tokito M.K. Lanahan A. Worley P. Holzbaur E.L.F. Ross C.A. Hum. Mol. Genet. 1997; 6: 2205-2212Crossref PubMed Scopus (275) Google Scholar) and a variety of intracellular organelles (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar, 21Gutekunst C.A. Li S.H. Yi H. Ferrante R.J. Li X.J. Hersch S.M. Soc. Neurosci. Abstr. 1997; 23: 1911Google Scholar, 22Martin E.J. Kim M. Velier J. Lee H.S. Chase K. Won L.A. Bhide P.G. Heller A. Aronin N. DiFiglia M. Soc. Neurosci. Abstr. 1997; 23: 1910Google Scholar). It will be interesting to investigate whether hHAP and huntingtin play roles in intracellular organelle transport. Huntingtin is the protein product of the gene for Huntington's disease (HD). 1The abbreviations used are: HD, Huntington's disease; HAP1, huntingtin-associated protein; hHAP, human huntingtin-associated protein; GST, glutathioneS-transferase; DRPLA, dentatorubral and pallidoluysian atrophy; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; PBS, phosphate-buffered saline; RT, reverse transcriptase; PAGE, polyacrylamide gel electrophoresis; kb, kilobase(s). 1The abbreviations used are: HD, Huntington's disease; HAP1, huntingtin-associated protein; hHAP, human huntingtin-associated protein; GST, glutathioneS-transferase; DRPLA, dentatorubral and pallidoluysian atrophy; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; PBS, phosphate-buffered saline; RT, reverse transcriptase; PAGE, polyacrylamide gel electrophoresis; kb, kilobase(s). The N terminus of human huntingtin contains a glutamine stretch encoded by a CAG repeat (1HD Collaborative Research Group Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (6956) Google Scholar). Expansion of the CAG/glutamine repeat (>37 units) causes HD (1HD Collaborative Research Group Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (6956) Google Scholar) and the length of the CAG repeat is inversely correlated with the age of onset of HD (2Duyao M.P. Taylor S.A. Buckler A.J. Ambrose C.M. Lin C. Groot N. Church D. Barnes G. Wasmuth J.J. Housman D.E. et al.Hum. Mol. Genet. 1993; 2: 673-676Crossref PubMed Scopus (20) Google Scholar, 3Andrew S.E. Goldberg Y.P. Kremer B. Telenius H. Theilmann J. Adam S. Starr E. Squitieri F. Lin B. Kalchman M.A. et al.Nat. Genet. 1993; 4: 398-403Crossref PubMed Scopus (867) Google Scholar, 4Stine O.C. Pleasant N. Franz M.L. Abbott M.H. Folstein S.E. Ross C.A. Hum. Mol. Genet. 1993; 2: 1547-1549Crossref PubMed Scopus (212) Google Scholar). Although the genetic basis of HD has been identified, its pathogenesis remains unclear. The widespread expression of huntingtin does not explain the selective neuropathology of HD, which is characterized by massive neuronal loss specifically in the basal ganglia (5Martin J.B. Gusella J.F. N. Engl. J. Med. 1986; 315: 1267-1276Crossref PubMed Scopus (15) Google Scholar, 6Vonsattel J.P. Myers R.H. Stevens T.J. Ferrante R.J. Bird E.D. Richardson Jr., E.P. J. Neuropathol. Exp. Neurol. 1985; 44: 559-577Crossref PubMed Scopus (2054) Google Scholar, 7Ferrante R.J. Kowall N.W. Beal M.F. Richardson Jr., E.P. Bird E.D. Martin J.B. Science. 1985; 230: 561-563Crossref PubMed Scopus (670) Google Scholar). Since mice that lack huntingtin or express reduced levels of huntingtin display aberrant brain development and perinatal lethality (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar), huntingtin is thought to be important for neurogenesis. However, loss of huntingtin activity is unlikely the cause of HD because heterozygous HD inactivation by translocation in man (9Ambrose C.M. Duyao M.P. Barnes G. Bates G.P. Lin C.S. Srinidhi J. Baxendale S. Hummerich H. Lehrach H. Altherr M. et al.Somat. Cell Mol. Genet. 1994; 20: 27-38Crossref PubMed Scopus (225) Google Scholar) or by targeted mutagenesis of the mouse HD gene (10Duyao M.P. Auerbach A.B. Ryan A. Persichetti F. Barnes G.T. McNeil S.M. Ge P. Vonsattel J.P. Gusella J.F. Joyner A.L. et al.Science. 1995; 269: 407-410Crossref PubMed Scopus (565) Google Scholar, 11Nasir J. Floresco S.B. O'Kusky J.R. Diewert V.M. Richman J.M. Zeisler J. Borowski A. Marth J.D. Phillips A.G. Hayden M.R. Cell. 1995; 81: 811-823Abstract Full Text PDF PubMed Scopus (667) Google Scholar) does not cause any HD phenotype. A gain of function model for the disease is thus widely accepted. It has been proposed that the expanded glutamine repeat may induce an abnormal interaction between the mutant protein and other cellular proteins (12Albin R.L. Tagle D.A. Trends Neurosci. 1995; 18: 11-14Abstract Full Text PDF PubMed Scopus (132) Google Scholar, 13Ross C.A. Neuron. 1995; 15: 493-496Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 14MacDonald M.E. Gusella J.F. Curr. Opin. Neurobiol. 1996; 6: 638-643Crossref PubMed Scopus (86) Google Scholar). Consistent with this idea, studies to date have shown that huntingtin interacts with several proteins including HAP1 (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar), glyceraldehyde phosphate dehydrogenase (GAPDH) (16Burke J.R. Enghild J.J. Martin M.E. Jou Y.S. Myers R.M. Roses A.D. Vance J.M. Strittmatter W.J. Nat. Med. 1996; 2: 347-350Crossref PubMed Scopus (403) Google Scholar), an unidentified calmodulin-associated protein (17Bao J. Sharp A.H. Wagster M.V. Becher M. Schilling G. Ross C.A. Dawson V.L. Dawson T.M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5037-5042Crossref PubMed Scopus (131) Google Scholar), and a protein homologous to the yeast cytoskeleton-associated protein Sla2p (HIP1) (18Kalchman M.A. Koide H.B. McCutcheon K. Graham R.K. Nichol K. Nishiyama K. Kazemi-Esfarjani P. Lynn F.C. Wellington C. Metzler M. Goldberg Y.P. Kanazawa I. Gietz R.D. Hayden M.R. Nat. Genet. 1997; 16: 44-53Crossref PubMed Scopus (317) Google Scholar, 19Wanker E.E. Rovira C. Scherzinger E. Hasenbank R. Walter S. Tait D. Colicelli J. Lehrach H. Hum. Mol. Genet. 1997; 6: 487-495Crossref PubMed Scopus (289) Google Scholar). These huntingtin-associated proteins are likely involved in HD pathology because their interactions with huntingtin are affected by an expanded glutamine repeat. HAP1 was first identified in rat brain and was found to bind to the N-terminal region of human huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar). It binds more tightly to mutant huntingtin than to normal huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar). Furthermore, rat HAP1 is specifically expressed in neurons (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar), making it a good candidate to be involved in the neuropathology of HD. Recent studies also show that rat HAP1 associates with a number of intracellular organelles (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar, 21Gutekunst C.A. Li S.H. Yi H. Ferrante R.J. Li X.J. Hersch S.M. Soc. Neurosci. Abstr. 1997; 23: 1911Google Scholar, 22Martin E.J. Kim M. Velier J. Lee H.S. Chase K. Won L.A. Bhide P.G. Heller A. Aronin N. DiFiglia M. Soc. Neurosci. Abstr. 1997; 23: 1910Google Scholar), moves with huntingtin in nerve fibers (23Block-Galarza J. Chase K.O. Sapp E. Vaughn K.T. Vallee R.B. DiFiglia M. Aronin N. Neuroreport. 1997; 8: 2247-2251Crossref PubMed Scopus (120) Google Scholar), and interacts with dynactin P150Glued (24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar, 25Engelender S. Sharp A.H. Colomer V. Tokito M.K. Lanahan A. Worley P. Holzbaur E.L.F. Ross C.A. Hum. Mol. Genet. 1997; 6: 2205-2212Crossref PubMed Scopus (275) Google Scholar) which participates in dynein-mediated retrograde transport. It remains to be shown whether human brain also contains a HAP1 homologue with similar binding properties. Since mice with normal levels of mutant huntingtin do not display any abnormal phenotype (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar), specific properties of the proteins which associate with human huntingtin may account for the HD phenotype that occurs in man. Therefore, it will be interesting to identify human proteins that associate with huntingtin. In this study, we isolated a human HAP1 homologue (hHAP) by molecular cloning. hHAP shares 62% amino acid identity with rat HAP1-A. Although its binding to huntingtin is comparable to that of rat HAP1, hHAP only has a single major form expressed in primate brains, in contrast to two isoforms of HAP1 in rat brain. The different sequences and expression of hHAP could contribute to a specific role in the interaction of hHAP and huntingtin in human brain. Identification of the human HAP1 homologue will facilitate the study of the relevance of the interaction between HAP1 and huntingtin in the pathology of HD. DISCUSSIONSeveral lines of evidence in the present study demonstrate that hHAP is a human counterpart of rat HAP1. First, the sequence of hHAP shows a high degree of homology to that of rat HAP1. Second, like rat HAP1 (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar), primate HAP1 is enriched in monkey and human brains. In addition, hHAP appears to be expressed with huntingtin in the neurons that are vulnerable in HD. Third, in vitro binding, immunoprecipitation, and coexpression studies consistently show that hHAP specifically interacts with huntingtin, and its in vitro binding seems to be enhanced by an expanded glutamine repeat. Rat HAP1 has been also found to bind more tightly to huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar). The similarity of hHAP and rat HAP1 in their sequences and binding to huntingtin suggests that hHAP and rat HAP1 bind to huntingtin in the same manner.There are also differences between hHAP and rat HAP1. The amino acid sequences of hHAP display a number of insertions or deletions when compared with the sequences of rat HAP1. Unlike huntingtin which is highly conserved between humans and rodents (91% amino acid identity), hHAP and rat HAP1 share 62% amino acid identity overall. However, amino acids in the huntingtin-binding regions of both proteins are well conserved (82% identity), suggesting that their binding properties are similar while other functional aspects may not be identical. In addition, unlike rat HAP1 which is expressed as two isoforms (HAP1-A and HAP1-B), hHAP only displays a single major form in primate brains. The expression pattern of hHAP in transfected cells is also different from that of rat HAP1-A. These differences may reflect unique properties of hHAP that could confer a specific role of the interaction of HAP1 and huntingtin in human brain.Several hHAP cDNA variants were found during cDNA screening. Most of them have insertions or deletions after the putative huntingtin-binding region. This may explain why no one has succeeded in isolating hHAP using yeast two-hybrid screening. However, the hHAP amino acid sequence presented in Fig. 1 is likely to represent the major protein product of the hHAP gene. This is because the cDNA probe and the antibody to the middle region of cloned hHAP consistently detect a major band on Northern and Western blots, respectively. Also, the mass of transfected hHAP is the same as that of native hHAP on Western blots. Several other weak bands are also seen. These weak bands could represent alternatively spliced products or other homologues of hHAP. Whether other hHAP cDNA variants are also expressed remains to be studied using antibodies specifically to their encoding amino acids.Identification of hHAP further suggests a potential role of HAP1 in the pathology of HD. First, the parallel reduction in the expression of huntingtin and hHAP in the HD brains suggests that both proteins are expressed in the same neurons that are vulnerable in HD. However, the expression of hHAP is not restricted to the brain regions that can be affected in HD. The selective neurodegeneration in HD may also be associated with heterogeneous expression of huntingtin in the striatum (32Ferrante R.J. Gutekunst C.A. Persichetti F. McNeil S.M. Kowall N.W. Gusella J.F. MacDonald M.E. Beal M.F. Hersch S.M. J. Neurosci. 1997; 17: 3052-3063Crossref PubMed Google Scholar) and/or other specific neuronal factors. Second, like rat HAP1, hHAP binds to the N-terminal region of huntingtin in vitro. Proteins that bind to the N-terminal region of huntingtin are especially interesting because the N-terminal fragment of huntingtin (amino acids 1–67) with an additional 150 glutamines has been found to cause neurological disorders in transgenic mice (31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar). We observed that the binding of the N-terminal huntingtin (amino acids 1–230) with the glutamine repeat (23Q, 44Q, or 73Q) to GST-hHAP is increased by lengthening the repeat. Although the increase is not dramatic in vitro, it could contribute to cumulative effects of huntingtin mutation or late onset of pathophysiology if it also occurs in vivo. The interaction of hHAP and huntingtin is also supported by their co-localization in hHAP immunoreactive inclusions in transfected cells. Their co-localization is specific because DRPLA, another glutamine repeat protein, does not co-localize with hHAP on these distinct structures. Rat HAP1 has been found to associate with similar cytoplasmic structures in the rat brain. 2C. A. Gutekunst, S-H. Li, X-J. Li, and S. M. Hersch, unpublished observations. Whether human brain also contains hHAP immunoreactive cytoplasmic inclusions remains to be studied.Unique components or specific properties of human huntingtin complexes may account for the neuropathology of HD in man. This is suggested by recent findings that transgenic mice expressing mutant human huntingtin do not display the graded loss of neurons in brain (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar, 31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar) that is the hallmark of human HD disease (5Martin J.B. Gusella J.F. N. Engl. J. Med. 1986; 315: 1267-1276Crossref PubMed Scopus (15) Google Scholar, 6Vonsattel J.P. Myers R.H. Stevens T.J. Ferrante R.J. Bird E.D. Richardson Jr., E.P. J. Neuropathol. Exp. Neurol. 1985; 44: 559-577Crossref PubMed Scopus (2054) Google Scholar, 7Ferrante R.J. Kowall N.W. Beal M.F. Richardson Jr., E.P. Bird E.D. Martin J.B. Science. 1985; 230: 561-563Crossref PubMed Scopus (670) Google Scholar). It is possible that expansion of the huntingtin glutamine repeat may alter specific properties of human huntingtin-associated proteins, such as hHAP, and this alteration could contribute to the neuropathology of HD in man. Identification of hHAP will promote the study of the potential role of the interaction of HAP1 and huntingtin in the pathology of HD. hHAP may also be involved in the normal function of human huntingtin. This is suggested by recent studies showing that rat HAP1 associates with dynactin P150Glued (24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar, 25Engelender S. Sharp A.H. Colomer V. Tokito M.K. Lanahan A. Worley P. Holzbaur E.L.F. Ross C.A. Hum. Mol. Genet. 1997; 6: 2205-2212Crossref PubMed Scopus (275) Google Scholar) and a variety of intracellular organelles (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar, 21Gutekunst C.A. Li S.H. Yi H. Ferrante R.J. Li X.J. Hersch S.M. Soc. Neurosci. Abstr. 1997; 23: 1911Google Scholar, 22Martin E.J. Kim M. Velier J. Lee H.S. Chase K. Won L.A. Bhide P.G. Heller A. Aronin N. DiFiglia M. Soc. Neurosci. Abstr. 1997; 23: 1910Google Scholar). It will be interesting to investigate whether hHAP and huntingtin play roles in intracellular organelle transport. Several lines of evidence in the present study demonstrate that hHAP is a human counterpart of rat HAP1. First, the sequence of hHAP shows a high degree of homology to that of rat HAP1. Second, like rat HAP1 (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar), primate HAP1 is enriched in monkey and human brains. In addition, hHAP appears to be expressed with huntingtin in the neurons that are vulnerable in HD. Third, in vitro binding, immunoprecipitation, and coexpression studies consistently show that hHAP specifically interacts with huntingtin, and its in vitro binding seems to be enhanced by an expanded glutamine repeat. Rat HAP1 has been also found to bind more tightly to huntingtin (15Li X.J. Li S.H. Sharp A.H. Nucifora Jr., F.C. Schilling G. Lanahan A. Worley P. Snyder S.H. Ross C.A. Nature. 1995; 378: 398-402Crossref PubMed Scopus (534) Google Scholar, 24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar). The similarity of hHAP and rat HAP1 in their sequences and binding to huntingtin suggests that hHAP and rat HAP1 bind to huntingtin in the same manner. There are also differences between hHAP and rat HAP1. The amino acid sequences of hHAP display a number of insertions or deletions when compared with the sequences of rat HAP1. Unlike huntingtin which is highly conserved between humans and rodents (91% amino acid identity), hHAP and rat HAP1 share 62% amino acid identity overall. However, amino acids in the huntingtin-binding regions of both proteins are well conserved (82% identity), suggesting that their binding properties are similar while other functional aspects may not be identical. In addition, unlike rat HAP1 which is expressed as two isoforms (HAP1-A and HAP1-B), hHAP only displays a single major form in primate brains. The expression pattern of hHAP in transfected cells is also different from that of rat HAP1-A. These differences may reflect unique properties of hHAP that could confer a specific role of the interaction of HAP1 and huntingtin in human brain. Several hHAP cDNA variants were found during cDNA screening. Most of them have insertions or deletions after the putative huntingtin-binding region. This may explain why no one has succeeded in isolating hHAP using yeast two-hybrid screening. However, the hHAP amino acid sequence presented in Fig. 1 is likely to represent the major protein product of the hHAP gene. This is because the cDNA probe and the antibody to the middle region of cloned hHAP consistently detect a major band on Northern and Western blots, respectively. Also, the mass of transfected hHAP is the same as that of native hHAP on Western blots. Several other weak bands are also seen. These weak bands could represent alternatively spliced products or other homologues of hHAP. Whether other hHAP cDNA variants are also expressed remains to be studied using antibodies specifically to their encoding amino acids. Identification of hHAP further suggests a potential role of HAP1 in the pathology of HD. First, the parallel reduction in the expression of huntingtin and hHAP in the HD brains suggests that both proteins are expressed in the same neurons that are vulnerable in HD. However, the expression of hHAP is not restricted to the brain regions that can be affected in HD. The selective neurodegeneration in HD may also be associated with heterogeneous expression of huntingtin in the striatum (32Ferrante R.J. Gutekunst C.A. Persichetti F. McNeil S.M. Kowall N.W. Gusella J.F. MacDonald M.E. Beal M.F. Hersch S.M. J. Neurosci. 1997; 17: 3052-3063Crossref PubMed Google Scholar) and/or other specific neuronal factors. Second, like rat HAP1, hHAP binds to the N-terminal region of huntingtin in vitro. Proteins that bind to the N-terminal region of huntingtin are especially interesting because the N-terminal fragment of huntingtin (amino acids 1–67) with an additional 150 glutamines has been found to cause neurological disorders in transgenic mice (31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar). We observed that the binding of the N-terminal huntingtin (amino acids 1–230) with the glutamine repeat (23Q, 44Q, or 73Q) to GST-hHAP is increased by lengthening the repeat. Although the increase is not dramatic in vitro, it could contribute to cumulative effects of huntingtin mutation or late onset of pathophysiology if it also occurs in vivo. The interaction of hHAP and huntingtin is also supported by their co-localization in hHAP immunoreactive inclusions in transfected cells. Their co-localization is specific because DRPLA, another glutamine repeat protein, does not co-localize with hHAP on these distinct structures. Rat HAP1 has been found to associate with similar cytoplasmic structures in the rat brain. 2C. A. Gutekunst, S-H. Li, X-J. Li, and S. M. Hersch, unpublished observations. Whether human brain also contains hHAP immunoreactive cytoplasmic inclusions remains to be studied. Unique components or specific properties of human huntingtin complexes may account for the neuropathology of HD in man. This is suggested by recent findings that transgenic mice expressing mutant human huntingtin do not display the graded loss of neurons in brain (8White J.K. Auerbach W. Duyao M.P. Vonsattel J.P. Gusella J.F. Joyner A.L. MacDonald M.E. Nat. Genet. 1997; 17: 404-410Crossref PubMed Scopus (415) Google Scholar, 31Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Lawton M. Trottier Y. Lehrach H. Davies S.W. Bates G.P. Cell. 1996; 87: 493-506Abstract Full Text Full Text PDF PubMed Scopus (2555) Google Scholar, 33Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Cell. 1997; 90: 537-548Abstract Full Text Full Text PDF PubMed Scopus (1889) Google Scholar) that is the hallmark of human HD disease (5Martin J.B. Gusella J.F. N. Engl. J. Med. 1986; 315: 1267-1276Crossref PubMed Scopus (15) Google Scholar, 6Vonsattel J.P. Myers R.H. Stevens T.J. Ferrante R.J. Bird E.D. Richardson Jr., E.P. J. Neuropathol. Exp. Neurol. 1985; 44: 559-577Crossref PubMed Scopus (2054) Google Scholar, 7Ferrante R.J. Kowall N.W. Beal M.F. Richardson Jr., E.P. Bird E.D. Martin J.B. Science. 1985; 230: 561-563Crossref PubMed Scopus (670) Google Scholar). It is possible that expansion of the huntingtin glutamine repeat may alter specific properties of human huntingtin-associated proteins, such as hHAP, and this alteration could contribute to the neuropathology of HD in man. Identification of hHAP will promote the study of the potential role of the interaction of HAP1 and huntingtin in the pathology of HD. hHAP may also be involved in the normal function of human huntingtin. This is suggested by recent studies showing that rat HAP1 associates with dynactin P150Glued (24Li S.-H. Gutekunst C.A. Hersch S.M. Li X.-J. J. Neurosci. 1998; 18: 1261-1269Crossref PubMed Google Scholar, 25Engelender S. Sharp A.H. Colomer V. Tokito M.K. Lanahan A. Worley P. Holzbaur E.L.F. Ross C.A. Hum. Mol. Genet. 1997; 6: 2205-2212Crossref PubMed Scopus (275) Google Scholar) and a variety of intracellular organelles (20Li X.J. Sharp A.H. Li S.H. Dawson T.M. Snyder S.H. Ross C.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4839-4844Crossref PubMed Scopus (123) Google Scholar, 21Gutekunst C.A. Li S.H. Yi H. Ferrante R.J. Li X.J. Hersch S.M. Soc. Neurosci. Abstr. 1997; 23: 1911Google Scholar, 22Martin E.J. Kim M. Velier J. Lee H.S. Chase K. Won L.A. Bhide P.G. Heller A. Aronin N. DiFiglia M. Soc. Neurosci. Abstr. 1997; 23: 1910Google Scholar). It will be interesting to investigate whether hHAP and huntingtin play roles in intracellular organelle transport. We are grateful to Dr. Gillian Bates for providing a λ phage DNA containing exon 1 of the human HD gene with 150 CAG repeats. We thank Dr. Richard Kahn for providing antibodies and Dr. Dean Danner for comments on the manuscript. A human HAP1 homologue. Cloning, expression, and interaction with Huntingtin.Journal of Biological ChemistryVol. 274Issue 14PreviewThe following acknowledgment was inadvertently omitted. Full-Text PDF Open Access" @default.
W2008202443 created "2016-06-24" @default.
W2008202443 creator A5009240555 @default.
W2008202443 creator A5026075478 @default.
W2008202443 creator A5032351341 @default.
W2008202443 creator A5042330021 @default.
W2008202443 creator A5088284887 @default.
W2008202443 date "1998-07-01" @default.
W2008202443 modified "2023-10-16" @default.
W2008202443 title "A Human HAP1 Homologue" @default.
W2008202443 cites W1509279614 @default.
W2008202443 cites W1786914655 @default.
W2008202443 cites W1966435810 @default.
W2008202443 cites W1973055895 @default.
W2008202443 cites W1977983193 @default.
W2008202443 cites W1978104052 @default.
W2008202443 cites W1983511812 @default.
W2008202443 cites W2000350637 @default.
W2008202443 cites W2002644780 @default.
W2008202443 cites W2010860283 @default.
W2008202443 cites W2012481532 @default.
W2008202443 cites W2013063789 @default.
W2008202443 cites W2020227900 @default.
W2008202443 cites W2020619883 @default.
W2008202443 cites W2024472839 @default.
W2008202443 cites W2029948374 @default.
W2008202443 cites W2030410903 @default.
W2008202443 cites W2042716629 @default.
W2008202443 cites W2043501837 @default.
W2008202443 cites W2044559546 @default.
W2008202443 cites W2062682951 @default.
W2008202443 cites W2069389331 @default.
W2008202443 cites W2069850109 @default.
W2008202443 cites W2082056883 @default.
W2008202443 cites W2090286778 @default.
W2008202443 cites W2112072636 @default.
W2008202443 cites W2121642311 @default.
W2008202443 cites W2137374371 @default.
W2008202443 cites W2156886710 @default.
W2008202443 cites W2159269805 @default.
W2008202443 cites W2266315341 @default.
W2008202443 doi "https://doi.org/10.1074/jbc.273.30.19220" @default.
W2008202443 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9668110" @default.
W2008202443 hasPublicationYear "1998" @default.
W2008202443 type Work @default.
W2008202443 sameAs 2008202443 @default.
W2008202443 citedByCount "65" @default.
W2008202443 countsByYear W20082024432012 @default.
W2008202443 countsByYear W20082024432013 @default.
W2008202443 countsByYear W20082024432014 @default.
W2008202443 countsByYear W20082024432015 @default.
W2008202443 countsByYear W20082024432016 @default.
W2008202443 countsByYear W20082024432017 @default.
W2008202443 countsByYear W20082024432018 @default.
W2008202443 countsByYear W20082024432019 @default.
W2008202443 countsByYear W20082024432020 @default.
W2008202443 countsByYear W20082024432021 @default.
W2008202443 countsByYear W20082024432022 @default.
W2008202443 countsByYear W20082024432023 @default.
W2008202443 crossrefType "journal-article" @default.
W2008202443 hasAuthorship W2008202443A5009240555 @default.
W2008202443 hasAuthorship W2008202443A5026075478 @default.
W2008202443 hasAuthorship W2008202443A5032351341 @default.
W2008202443 hasAuthorship W2008202443A5042330021 @default.
W2008202443 hasAuthorship W2008202443A5088284887 @default.
W2008202443 hasConcept C185592680 @default.
W2008202443 hasConcept C41008148 @default.
W2008202443 hasConcept C70721500 @default.
W2008202443 hasConcept C86803240 @default.
W2008202443 hasConceptScore W2008202443C185592680 @default.
W2008202443 hasConceptScore W2008202443C41008148 @default.
W2008202443 hasConceptScore W2008202443C70721500 @default.
W2008202443 hasConceptScore W2008202443C86803240 @default.
W2008202443 hasIssue "30" @default.
W2008202443 hasLocation W20082024431 @default.
W2008202443 hasOpenAccess W2008202443 @default.
W2008202443 hasPrimaryLocation W20082024431 @default.
W2008202443 hasRelatedWork W1531601525 @default.
W2008202443 hasRelatedWork W1990781990 @default.
W2008202443 hasRelatedWork W2319480705 @default.
W2008202443 hasRelatedWork W2384464875 @default.
W2008202443 hasRelatedWork W2606230654 @default.
W2008202443 hasRelatedWork W2607424097 @default.
W2008202443 hasRelatedWork W2748952813 @default.
W2008202443 hasRelatedWork W2899084033 @default.
W2008202443 hasRelatedWork W2948807893 @default.
W2008202443 hasRelatedWork W2778153218 @default.
W2008202443 hasVolume "273" @default.
W2008202443 isParatext "false" @default.
W2008202443 isRetracted "false" @default.
W2008202443 magId "2008202443" @default.
W2008202443 workType "article" @default.