nuclear mutant
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2020 ◽  
Vol 29 (15) ◽  
pp. 2596-2610
Author(s):  
Julia E Gerson ◽  
Nathaniel Safren ◽  
Svetlana Fischer ◽  
Ronak Patel ◽  
Emily V Crowley ◽  
...  

Abstract Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.



Glia ◽  
2016 ◽  
Vol 65 (1) ◽  
pp. 50-61 ◽  
Author(s):  
Anne H.P. Jansen ◽  
Maurik van Hal ◽  
Ilse C. op den Kelder ◽  
Romy T. Meier ◽  
Anna-Aster de Ruiter ◽  
...  


2013 ◽  
Vol 12 (3) ◽  
pp. 138-145
Author(s):  
Justina Boloebi Porbeni ◽  
Iyiola Fawole ◽  
Christopher Alake
Keyword(s):  


2010 ◽  
Vol 9 (5) ◽  
pp. 565-574 ◽  
Author(s):  
Laure Michelet ◽  
Linnka Lefebvre-Legendre ◽  
Sarah E. Burr ◽  
Jean-David Rochaix ◽  
Michel Goldschmidt-Clermont


2006 ◽  
Vol 15 (12) ◽  
pp. 2015-2024 ◽  
Author(s):  
Alejandro Lloret ◽  
Ella Dragileva ◽  
Allison Teed ◽  
Janice Espinola ◽  
Elisa Fossale ◽  
...  


2005 ◽  
Vol 117 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Richard G. PICCIONI ◽  
Nam-Hai CHUA ◽  
Pierre BENNOUN


2001 ◽  
Vol 158 (8) ◽  
pp. 1069-1075 ◽  
Author(s):  
Amybeth Cohen ◽  
Christopher B. Yohn ◽  
Stephen P. Mayfield


2000 ◽  
Vol 21 (3) ◽  
pp. 269-280 ◽  
Author(s):  
Judy Brangeon ◽  
Mohammed Sabar ◽  
Sophie Gutierres ◽  
Bruno Combettes ◽  
Jérôme Bove ◽  
...  




Genetics ◽  
1997 ◽  
Vol 145 (2) ◽  
pp. 467-478 ◽  
Author(s):  
Rodger Voelker ◽  
Janet Mendel-Hartvig ◽  
Alice Barkan

A nuclear mutant of maize, tha1, which exhibited defects in the translocation of proteins across the thylakoid membrane, was described previously. A transposon insertion at the tha1 locus facilitated the cloning of portions of the tha1 gene. Strong sequence similarity with secA genes from bacteria, pea and spinach indicates that tha1 encodes a SecA homologue (cp-SecA). The tha1-ref allele is either null or nearly so, in that tha1 mRNA is undetectable in mutant leaves and cp-SecA accumulation is reduced ≥40-fold. These results, in conjunction with the mutant phenotype described previously, demonstrate that cp-SecA functions in vivo to facilitate the translocation of OEC33, PSI-F and plastocyanin but does not function in the translocation of OEC23 and OEC16. Our results confirm predictions for cp-Sed function made from the results of in vitro experiments and establish several new functions for cp-SecA, including roles in the targeting of a chloroplast-encoded protein, cytochrome f, and in protein targeting in the etioplast, a nonphotosynthetic plastid type. Our finding that the accumulation of properly targeted plastocyanin and cytochrome f in tha1-ref thylakoid membranes is reduced only a few-fold despite the near or complete absence of cp-SecA suggests that cp-SecA facilitates but is not essential in vivo for their translocation across the membrane.



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