Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
13 03 2020
13 03 2020
Historique:
received:
16
10
2019
revised:
06
12
2019
accepted:
07
01
2020
pubmed:
17
1
2020
medline:
4
6
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Huntington's disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ.
Identifiants
pubmed: 31943010
pii: 5701559
doi: 10.1093/hmg/ddaa001
pmc: PMC7608755
doi:
Substances chimiques
HTT protein, human
0
Huntingtin Protein
0
Peptides
0
polyglutamine
26700-71-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
674-688Subventions
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Hum Mol Genet. 1999 Mar;8(3):397-407
pubmed: 9949199
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12784-9
pubmed: 11675509
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13318-23
pubmed: 11687635
J Cell Biol. 1998 Jun 1;141(5):1097-105
pubmed: 9606203
J Neurosci. 2008 Jun 11;28(24):6182-95
pubmed: 18550760
Science. 1998 Jul 10;281(5374):269-72
pubmed: 9657724
Science. 1997 Sep 26;277(5334):1990-3
pubmed: 9302293
PLoS One. 2016 Jun 06;11(6):e0155747
pubmed: 27271685
EMBO J. 2015 Mar 12;34(6):778-97
pubmed: 25672362
Nat Commun. 2016 Dec 08;7:13821
pubmed: 27929117
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2366-70
pubmed: 23341618
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14610-5
pubmed: 23898200
Neurobiol Dis. 2001 Jun;8(3):405-18
pubmed: 11442350
J Biol Chem. 2016 Jun 3;291(23):12074-86
pubmed: 27002149
Nature. 2001 Oct 18;413(6857):739-43
pubmed: 11607033
Nucleic Acid Ther. 2014 Feb;24(1):4-12
pubmed: 24380395
Cell. 1998 Oct 2;95(1):55-66
pubmed: 9778247
Hum Mol Genet. 2000 Jan 1;9(1):13-25
pubmed: 10587574
Mol Ther. 2007 Aug;15(8):1444-51
pubmed: 17505477
Mol Cell Neurosci. 1999 Aug;14(2):121-8
pubmed: 10479410
J Biol Chem. 2010 Mar 19;285(12):8808-23
pubmed: 20086007
Dev Biol. 2019 Jan 1;445(1):37-53
pubmed: 30539716
J Cell Sci. 2009 Sep 15;122(Pt 18):3262-71
pubmed: 19690053
Neurotox Res. 2011 Aug;20(2):120-33
pubmed: 21116768
Curr Opin Cell Biol. 2014 Feb;26:139-146
pubmed: 24463332
Nat Struct Mol Biol. 2009 Apr;16(4):380-9
pubmed: 19270701
PLoS Genet. 2011 Jul;7(7):e1002087
pubmed: 21750678
Hum Mol Genet. 2014 May 1;23(9):2324-38
pubmed: 24334607
Hum Mol Genet. 2005 Oct 15;14(20):3065-78
pubmed: 16183657
Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4406-4411
pubmed: 28400517
Development. 2005 Sep;132(17):3935-46
pubmed: 16079158
Exp Neurol. 2012 Nov;238(1):1-11
pubmed: 22200539
J Neurosci. 2002 May 1;22(9):3473-83
pubmed: 11978824
Neurobiol Dis. 2006 May;22(2):346-56
pubmed: 16423528
Nat Struct Mol Biol. 2011 Mar;18(3):328-36
pubmed: 21317897
J Neurosci. 1999 Apr 1;19(7):2522-34
pubmed: 10087066
J Neuropathol Exp Neurol. 2007 Apr;66(4):313-20
pubmed: 17413322
Cell Cycle. 2010 Sep 1;9(17):3401-13
pubmed: 20703094
J Biol Chem. 2009 Apr 17;284(16):10855-67
pubmed: 19204007
Dev Biol. 2014 Jan 15;385(2):253-62
pubmed: 24247008
Cell. 1997 Aug 8;90(3):537-48
pubmed: 9267033
J Biol Chem. 2013 Jun 14;288(24):17225-37
pubmed: 23612975
Lancet Neurol. 2009 Aug;8(8):765-74
pubmed: 19608102
Nat Struct Mol Biol. 2009 Dec;16(12):1279-85
pubmed: 19915590
EMBO J. 2015 Sep 2;34(17):2255-71
pubmed: 26165689
Biochem Soc Trans. 1998 Aug;26(3):471-5
pubmed: 9765898
Lancet Neurol. 2011 Jan;10(1):83-98
pubmed: 21163446
Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16889-94
pubmed: 25385587
Hum Mol Genet. 2011 Apr 15;20(8):1633-42
pubmed: 21307087
Elife. 2016 Mar 22;5:e11184
pubmed: 27003594
Hum Mol Genet. 2015 Feb 15;24(4):913-25
pubmed: 25305076
Mol Cell. 2002 Aug;10(2):259-69
pubmed: 12191472
Cell Cycle. 2007 Dec 1;6(23):2970-81
pubmed: 18156806
J Biol Chem. 2000 Jun 30;275(26):19831-8
pubmed: 10770929
Hum Mol Genet. 1998 May;7(5):783-90
pubmed: 9536081
J Biol Chem. 2015 Jul 31;290(31):19287-306
pubmed: 26025364
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):660-6
pubmed: 16784720
PLoS Comput Biol. 2009 Mar;5(3):e1000304
pubmed: 19282972
Development. 2010 Jan;137(1):141-50
pubmed: 20023169
Cell. 1997 Aug 8;90(3):549-58
pubmed: 9267034
RNA Biol. 2013 Nov;10(11):1647-52
pubmed: 24256709
Gene. 1997 Jun 3;191(2):191-5
pubmed: 9218719
Development. 1993 Jun;118(2):401-15
pubmed: 8223268
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3312-7
pubmed: 17360644
Cell Res. 2010 Apr;20(4):400-7
pubmed: 20231860
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14516-7
pubmed: 23975930
J Huntingtons Dis. 2013;2(4):395-403
pubmed: 25062728
Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11402-7
pubmed: 16076956
Angew Chem Int Ed Engl. 2014 Feb 10;53(7):1928-33
pubmed: 24446188
Development. 2002 Jan;129(2):493-503
pubmed: 11807040
BMC Neurosci. 2005 Jan 13;6:1
pubmed: 15649316
Genesis. 2002 Sep-Oct;34(1-2):1-15
pubmed: 12324939
Methods Mol Biol. 2013;1017:41-57
pubmed: 23719906