Polyglutamine diseases: Protein cleavage and aggregation

Current Opinion in Neurobiology

Volumn 9, Issue 5, 1999, Pages 566-570

  Zoghbi, Huda Y ^a   Orr, Harry T ^b  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUTAMINE;

CELL NUCLEUS; DEGENERATIVE DISEASE; HUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN DEGRADATION; SHORT SURVEY;

EID: 0032824836     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(99)00013-6     Document Type: Review

References (36)

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15. •].
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19. Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL Evidence for HDJ-2/HSDJ proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet. 8:1999;673-682. Extends the localization of the proteasome to nuclear aggregates formed by mutant ataxin-3 (SCA3) and demonstrates that inhibition of proteasome activity in transfected cells increases aggregate formation.
20. Stenoien DL, Cummings CJ, Adams HP, Mancini MG, Patel K, DeMartino GN, Marcelli M, Weigel NL, Mancini MA Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet. 8:1999;731-741. Demonstrates that aggregates formed by an androgen receptor with 48 glutamines sequester chaperone protein and proteasome components. This study also shows that aggregate formation is suppressed by overexpression of the HDJ-2 chaperone.
21. Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, Singaraja R, Kazemi-Esfarjani P, Devon R, Kim SUet al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 18:1998;150-154. An interesting study that demonstrates the importance of mutant huntingtin truncation both for aggregate formation and for toxicity in transfected cells.
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24. Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol. 143:1998;1457-1470. Demonstrates that nuclear inclusions formed by mutant ataxin-3 fragments in a cellular model are able to recruit other polyglutamine proteins (i.e. ataxin-1 and full-length endogenous ataxin-3) into the aggregates. Most interesting is the author's demonstration that in a Drosophila model of polyglutamine disease, the TATA-binding protein is found in the nuclear inclusions.
25. Lunkes A, Mandel JL A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 7:1998;1355-1361. Presents a stable transfected cellular model of HD pathogenesis. With time, only cells transfected with a mutant full-length HD allele process the protein into fragments whose size is consistent with cleavage by caspase-3. A more truncated amino-terminal fragment of huntingtin was also detected. This fragment first appears in cytoplasmic inclusions and later in nuclear inclusions. A very nice cellular model for following the metabolism of mutant huntingtin at the biochemical level.
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29. Kim M, Lee H-S, LaForet G, McIntyre C, Martin EJ, Chang P, Kim TW, Williams M, Reddy PH, Tagle Det al. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci. 19:1999;964-973. Immortalized striatal cells were transfected with truncated and full-length wild-type and mutant huntingtin. Only mutant huntingtin formed aggregates, which contained cleaved amino-terminal products, the presence of which increased with time. Two caspase inhibitors were used to determine the effect of caspase cleavage on aggregate formation. Interestingly, these studies revealed that aggregate formation and cell death could be uncoupled in this model system.
30. Ona VO, Li M, Vonsattel JPG, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li X-J, Stieg PEet al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature. 399:1999;263-267. A very interesting study demonstrating a role of caspase-1 in disease progression in a transgenic mouse model of HD. Inhibition of caspase activity retarded all aspects of disease progression in this model, including the formation of nuclear aggregates containing the product of the HD exon 1 transgene.
31. Saudou F, Finkbeiner S, Devys D, Greenberg ME Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 95:1998;55-66. An important demonstration that in a striatal cell model system, huntingtin must enter the nucleus to be toxic. This study also found that cellular toxicity by mutant huntingtin is not dependent on the formation of aggregates and could be blocked by growth factors. Interestingly, this is the first report to suggest that aggregation of a mutant polyglutamine protein is protective to the cell.
32. Huynh DP, Del Bigio MR, Ho DH, Pulst SM Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2. Ann Neurol. 45:1999;232-241. The authors report that even though they found that ataxin-2 immunoreactivity is more intense in SCA2 brain material, they were not able to detect nuclear inclusions in SCA2 patient tissue. An important study that demonstrates that nuclear aggregates can be present in human patient material in the absence of detectable pathology.
33. ••] provide the first direct demonstrations unlinking polyglutamine aggregates from pathogenesis.
34. ••].
35. ••] report on two potentially very important mouse models of HD, both of which are based on the expression of a full-length version of huntingtin with an expanded glutamine tract. Both studies found striatal pathology similar to that seen in HD in the absence of nuclear aggregates.
36. Wilkinson MG, Millar JB SAPKs and transcription factors do the nucleocytoplasmic tango [comment]. Genes Dev. 12:1998;1391-1397.