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Article ; Online: A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy.

Atwal, Randy Singh / Truant, Ray

2007 Volume 4, Issue 1, Page(s) 91–93

Abstract: We have recently published the precise definition of an aminoterminal membrane association domain in huntingtin, capable of targeting to the endoplasmic reticulum and late endosomes as well as autophagic vesicles. In response to ER stress induced by ... ...

Abstract	We have recently published the precise definition of an aminoterminal membrane association domain in huntingtin, capable of targeting to the endoplasmic reticulum and late endosomes as well as autophagic vesicles. In response to ER stress induced by several pathways, huntingtin releases from membranes and rapidly translocates into the nucleus. Huntingtin is then capable of nuclear export and re-association with the ER in the absence of stress. This release is inhibited when huntingtin contains the polyglutamine expansion seen in Huntington's disease. As a result, mutant huntingtin expressing cells have a perturbed ER and an increase in autophagic vesicles. Here, we discuss the potential function of the huntingtin protein as an ER sentinel, potentially regulating autophagy in response to ER stress. We compare these recent findings to the well characterized mammalian target of rapamycin, mTor, a protein described over a decade ago as related to huntingtin structurally by leucine-rich, repetitive HEAT sequences. Since then, the described functional similarities between Huntingtin and mTor are striking, and this new information about huntingtin's direct association with autophagic vesicles indicates that this structural similarity may extend to functional similarities having an impact upon ER functionality and autophagy.
MeSH term(s)	Animals ; Autophagy/physiology ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/ultrastructure ; Humans ; Huntingtin Protein ; Huntington Disease/metabolism ; Huntington Disease/physiopathology ; Intracellular Membranes/metabolism ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oxidative Stress
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins
Language	English
Publishing date	2007-10-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.5201
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Article ; Online: Identification of a karyopherin β1/β2 proline-tyrosine nuclear localization signal in huntingtin protein.

Desmond, Carly R / Atwal, Randy Singh / Xia, Jianrun / Truant, Ray

The Journal of biological chemistry

2012 Volume 287, Issue 47, Page(s) 39626–39633

Abstract: Among the known pathways of protein nuclear import, the karyopherin β2/transportin pathway is only the second to have a defined nuclear localization signal (NLS) consensus. Huntingtin, a 350-kDa protein, has defined roles in the nucleus, as well as a ... ...

Abstract	Among the known pathways of protein nuclear import, the karyopherin β2/transportin pathway is only the second to have a defined nuclear localization signal (NLS) consensus. Huntingtin, a 350-kDa protein, has defined roles in the nucleus, as well as a CRM1/exportin-dependent nuclear export signal; however, the NLS and exact pathway of import have remained elusive. Here, using a live cell assay and affinity chromatography, we show that huntingtin has a karyopherin β2-dependent proline-tyrosine (PY)-NLS in the amino terminus of the protein. This NLS comprises three consensus components: a basic charged sequence, a downstream conserved arginine, and a PY sequence. Unlike the classic PY-NLS, which has an unstructured intervening sequence between the consensus components, we show that a β sheet structured region separating the consensus elements is critical for huntingtin NLS function. The huntingtin PY-NLS is also capable of import through the importin/karyopherin β1 pathway but was not functional in all cell types tested. We propose that this huntingtin PY-NLS may comprise a new class of multiple import factor-dependent NLSs with an internal structural component that may regulate NLS activity.
MeSH term(s)	Animals ; Humans ; Huntingtin Protein ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Localization Signals/physiology ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptide Mapping/methods ; Protein Structure, Secondary ; Protein Structure, Tertiary ; beta Karyopherins/genetics ; beta Karyopherins/metabolism
Chemical Substances	HTT protein, human ; Htt protein, mouse ; Huntingtin Protein ; KPNB1 protein, human ; Kpnb1 protein, mouse ; Nerve Tissue Proteins ; Nuclear Localization Signals ; Nuclear Proteins ; TNPO1 protein, human ; beta Karyopherins
Language	English
Publishing date	2012-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.412379
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Article: Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease.

Truant, Ray / Atwal, Randy Singh / Burtnik, Anjee

Progress in neurobiology

2007 Volume 83, Issue 4, Page(s) 211–227

Abstract: There are nine genetic neurodegenerative diseases caused by a similar genetic defect, a CAG DNA triplet-repeat expansion in the disease gene's open reading frame resulting in a polyglutamine expansion in the disease proteins. Despite the commonality of ... ...

Abstract	There are nine genetic neurodegenerative diseases caused by a similar genetic defect, a CAG DNA triplet-repeat expansion in the disease gene's open reading frame resulting in a polyglutamine expansion in the disease proteins. Despite the commonality of polyglutamine expansion, each of the polyglutamine diseases manifest as unique diseases, with some similarities, but important differences. These differences suggest that the context of the polyglutamine expansion is important to the mechanism of pathology of the disease proteins. Therefore, it is becoming increasingly paramount to understand the normal functions of these polyglutamine disease proteins, which include huntingtin, the polyglutamine-expanded protein in Huntington's disease (HD). Transcriptional dysregulation is seen in HD. Here we discuss the role of normal huntingtin in transcriptional regulation and misregulation in Huntington's disease in relation to potentially analogous model systems, and to other polyglutamine disease proteins. Huntingtin has functional roles in both the cytoplasm and the nucleus. One commonality of activity of polyglutamine disease proteins is at the level of protein dynamics and ability to import and export to and from the nucleus. Knowing the temporal location of huntingtin protein in response to signaling and neuronal communication could lead to valuable insights into an important trigger of HD pathology.
MeSH term(s)	Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; Glutamine/metabolism ; Humans ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptides/metabolism ; Transcription, Genetic/physiology
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; Glutamine (0RH81L854J) ; polyglutamine (26700-71-0)
Language	English
Publishing date	2007-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2006.11.004
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Article ; Online: Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.

Vijayvargia, Ravi / Epand, Raquel / Leitner, Alexander / Jung, Tae-Yang / Shin, Baehyun / Jung, Roy / Lloret, Alejandro / Singh Atwal, Randy / Lee, Hyeongseok / Lee, Jong-Min / Aebersold, Ruedi / Hebert, Hans / Song, Ji-Joon / Seong, Ihn Sik

eLife

2016 Volume 5, Page(s) e11184

Abstract: The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including ... ...

Abstract	The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.
MeSH term(s)	Biophysical Phenomena ; Circular Dichroism ; Huntingtin Protein/chemistry ; Huntingtin Protein/metabolism ; Mass Spectrometry ; Microscopy, Electron ; Peptides/metabolism ; Protein Conformation
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2016-03-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.11184
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Article: Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases.

Truant, Ray / Atwal, Randy Singh / Desmond, Carly / Munsie, Lise / Tran, Thu

The FEBS journal

2008 Volume 275, Issue 17, Page(s) 4252–4262

Abstract: After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated ... ...

Abstract	After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington's disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers, and that the protein context of expanded polyglutamine is critical to understanding disease specificity. Here we discuss recent publications that define other important therapeutic targets for polyglutamine-mediated neurodegeneration related to the context of the expanded polyglutamine tract in the disease protein.
MeSH term(s)	Humans ; Huntington Disease/genetics ; Huntington Disease/pathology ; Models, Theoretical ; Peptides/genetics
Chemical Substances	Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2008-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2008.06561.x
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Article ; Online: Kinase inhibitors modulate huntingtin cell localization and toxicity.

Atwal, Randy Singh / Desmond, Carly R / Caron, Nicholas / Maiuri, Tamara / Xia, Jianrun / Sipione, Simonetta / Truant, Ray

Nature chemical biology

2011 Volume 7, Issue 7, Page(s) 453–460

Abstract: Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of ... ...

Abstract	Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 affects N17 conformation and targets full-length huntingtin to chromatin-dependent subregions of the nucleus, the mitotic spindle and cleavage furrow during cell division. Polyglutamine-expanded mutant huntingtin is hypophosphorylated in N17 in both homozygous and heterozygous cell contexts. By high-content screening in live cells, we identified kinase inhibitors that modulated N17 phosphorylation and hence huntingtin subcellular localization. N17 phosphorylation was reduced by casein kinase-2 inhibitors. Paradoxically, IKKβ kinase inhibition increased N17 phosphorylation, affecting huntingtin nuclear and subnuclear localization. These data indicate that huntingtin phosphorylation at Ser13 and Ser16 can be modulated by small-molecule drugs, which may have therapeutic potential in Huntington's disease.
MeSH term(s)	Animals ; Blotting, Western ; Casein Kinase II/antagonists & inhibitors ; Cell Line ; Cell Nucleus/metabolism ; Cell Survival/drug effects ; Disease Models, Animal ; Endoplasmic Reticulum/metabolism ; Fluorescent Antibody Technique ; Huntingtin Protein ; Huntington Disease/enzymology ; Huntington Disease/genetics ; Huntington Disease/metabolism ; I-kappa B Kinase/antagonists & inhibitors ; Mice ; Mutation ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/genetics ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Serine/genetics ; Spindle Apparatus/metabolism ; Transfection
Chemical Substances	Htt protein, mouse ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins ; Protein Kinase Inhibitors ; Serine (452VLY9402) ; Casein Kinase II (EC 2.7.11.1) ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2011-05-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio.582
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Article ; Online: Mutant huntingtin causes defective actin remodeling during stress: defining a new role for transglutaminase 2 in neurodegenerative disease.

Munsie, Lise / Caron, Nicholas / Atwal, Randy Singh / Marsden, Ian / Wild, Edward J / Bamburg, James R / Tabrizi, Sarah J / Truant, Ray

Human molecular genetics

2011 Volume 20, Issue 10, Page(s) 1937–1951

Abstract: Huntington's disease (HD) is caused by an expanded CAG tract in the Interesting transcript 15 (IT15) gene encoding the 350 kDa huntingtin protein. Cellular stresses can trigger the release of huntingtin from the endoplasmic reticulum, allowing huntingtin ...

Abstract	Huntington's disease (HD) is caused by an expanded CAG tract in the Interesting transcript 15 (IT15) gene encoding the 350 kDa huntingtin protein. Cellular stresses can trigger the release of huntingtin from the endoplasmic reticulum, allowing huntingtin nuclear entry. Here, we show that endogenous, full-length huntingtin localizes to nuclear cofilin-actin rods during stress and is required for the proper stress response involving actin remodeling. Mutant huntingtin induces a dominant, persistent nuclear rod phenotype similar to that described in Alzheimer's disease for cytoplasmic cofilin-actin rods. Using live cell temporal studies, we show that this stress response is similarly impaired when mutant huntingtin is present, or when normal huntingtin levels are reduced. In clinical lymphocyte samples from HD patients, we have quantitatively detected cross-linked complexes of actin and cofilin with complex formation varying in correlation with disease progression. By live cell fluorescence lifetime imaging measurement-Förster resonant energy transfer studies and western blot assays, we quantitatively observed that stress-activated tissue transglutaminase 2 (TG2) is responsible for the actin-cofilin covalent cross-linking observed in HD. These data support a direct role for huntingtin in nuclear actin re-organization, and describe a new pathogenic mechanism for aberrant TG2 enzymatic hyperactivity in neurodegenerative diseases.
MeSH term(s)	Actin Depolymerizing Factors/metabolism ; Actins/metabolism ; Animals ; Cell Line ; Cytoskeletal Proteins/metabolism ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Gene Expression/genetics ; Heat-Shock Response/genetics ; Hot Temperature ; Humans ; Huntingtin Protein ; Huntington Disease/enzymology ; Huntington Disease/genetics ; Intracellular Space/metabolism ; Lymphocytes/metabolism ; Mice ; Models, Biological ; Mutation/genetics ; NIH 3T3 Cells ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Transport ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Transglutaminases/genetics ; Transglutaminases/metabolism
Chemical Substances	Actin Depolymerizing Factors ; Actins ; Cytoskeletal Proteins ; Htt protein, mouse ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins ; RNA, Small Interfering ; transglutaminase 2 (EC 2.3.2.-) ; Transglutaminases (EC 2.3.2.13) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2011-02-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddr075
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Article: Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity.

Atwal, Randy Singh / Xia, Jianrun / Pinchev, Deborah / Taylor, Jillian / Epand, Richard M / Truant, Ray

Human molecular genetics

2007 Volume 16, Issue 21, Page(s) 2600–2615

Abstract: Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane- ... ...

Abstract	Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER). The association of huntingtin to the ER is affected by ER stress. A single point mutation in huntingtin 1-18 predicted to disrupt this helical structure displayed striking phenotypes of complete inhibition of polyglutamine-mediated aggregation, increased huntingtin nuclear accumulation and greatly increased mutant huntingtin toxicity in a striatal-derived mouse cell line. Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. We propose that huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events. The increased nuclear entry of mutant huntingtin due to loss of ER-targeting results in increased toxicity.
MeSH term(s)	Amino Acid Sequence ; Animals ; Autophagy ; Cell Line ; Cell Nucleus/chemistry ; Cell Nucleus/metabolism ; Conserved Sequence ; Endoplasmic Reticulum/chemistry ; Endoplasmic Reticulum/metabolism ; Endosomes/chemistry ; Endosomes/metabolism ; Huntingtin Protein ; Huntington Disease/metabolism ; Mice ; Molecular Sequence Data ; Mutation ; Nerve Tissue Proteins/analysis ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Localization Signals/genetics ; Nuclear Localization Signals/metabolism ; Nuclear Proteins/analysis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary
Chemical Substances	Htt protein, mouse ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Localization Signals ; Nuclear Proteins
Language	English
Publishing date	2007-11-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddm217
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Article ; Online: Huntingtin’s spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

Ravi Vijayvargia / Raquel Epand / Alexander Leitner / Tae-Yang Jung / Baehyun Shin / Roy Jung / Alejandro Lloret / Randy Singh Atwal / Hyeongseok Lee / Jong-Min Lee / Ruedi Aebersold / Hans Hebert / Ji-Joon Song / Ihn Sik Seong

eLife, Vol

2016 Volume 5

Abstract: The polyglutamine expansion in huntingtin protein causes Huntington’s disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including ... ...

Abstract	The polyglutamine expansion in huntingtin protein causes Huntington’s disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.
Keywords	Huntington's disease ; HEAT/HEAT-like repeat ; neurodegenerative disorders ; solenoid scaffold protein ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2016-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article: Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases

Truant, Ray / Atwal, Randy Singh / Desmond, Carly / Munsie, Lise / Tran, Thu

FEBS journal. 2008 Sept., v. 275, no. 17

2008

Abstract	After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington's disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers, and that the protein context of expanded polyglutamine is critical to understanding disease specificity. Here we discuss recent publications that define other important therapeutic targets for polyglutamine-mediated neurodegeneration related to the context of the expanded polyglutamine tract in the disease protein.
Language	English
Dates of publication	2008-09
Size	p. 4252-4262.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2008.06561.x
Database	NAL-Catalogue (AGRICOLA)

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