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Article ; Online: Monitoring of Chromatin Organization at the Nuclear Pore Complex, Inner Nuclear Membrane, and Nuclear Interior in Live Cells by Fluorescence Ratiometric Imaging of Chromatin (FRIC).

Niss, Frida / Bergqvist, Cecilia / Ström, Anna-Lena / Hallberg, Einar

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2502, Page(s) 151–160

Abstract: The image analysis tool FRIC (Fluorescence Ratiometric Imaging of Chromatin) quantitatively monitors dynamic spatiotemporal distribution of euchromatin and total chromatin in live cells. A vector (pTandemH) assures stoichiometrically constant expression ... ...

Abstract	The image analysis tool FRIC (Fluorescence Ratiometric Imaging of Chromatin) quantitatively monitors dynamic spatiotemporal distribution of euchromatin and total chromatin in live cells. A vector (pTandemH) assures stoichiometrically constant expression of the histone variants Histone 3.3 and Histone 2B, fused to EGFP and mCherry, respectively. Quantitative ratiometric (H3.3/H2B) imaging displayed a concentrated distribution of heterochromatin in the periphery of U2OS cell nuclei. As a proof of concept, peripheral heterochromatin responded to experimental manipulation of histone acetylation as well as expression of the mutant lamin A protein "progerin," which causes Hutchinson-Gilford Progeria Syndrome. In summary FRIC is versatile, unbiased, robust, requires a minimum of experimental steps and is suitable for screening purposes.
MeSH term(s)	Cell Nucleus/metabolism ; Chromatin/genetics ; Chromatin/metabolism ; Fluorescence ; HeLa Cells ; Heterochromatin/metabolism ; Histones/metabolism ; Humans ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Nuclear Envelope/metabolism ; Nuclear Pore/metabolism
Chemical Substances	Chromatin ; Heterochromatin ; Histones ; Lamin Type A
Language	English
Publishing date	2022-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2337-4_10
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Article ; Online: Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 Are Altered by Polyglutamine-Expanded ATXN7.

Niss, Frida / Piñero-Paez, Laura / Zaidi, Wajiha / Hallberg, Einar / Ström, Anna-Lena

Molecular neurobiology

2022 Volume 59, Issue 8, Page(s) 5236–5251

Abstract: Spinocerebellar ataxia type 7 (SCA7) and other polyglutamine (polyQ) diseases are caused by expansions of polyQ repeats in disease-specific proteins. Aggregation of the polyQ proteins resulting in various forms of cellular stress, that could induce the ... ...

Abstract	Spinocerebellar ataxia type 7 (SCA7) and other polyglutamine (polyQ) diseases are caused by expansions of polyQ repeats in disease-specific proteins. Aggregation of the polyQ proteins resulting in various forms of cellular stress, that could induce the stress granule (SG) response, is believed to be a common pathological mechanism in these disorders. SGs can contribute to cell survival but have also been suggested to exacerbate disease pathology by seeding protein aggregation. In this study, we show that two SG-related proteins, TDP-43 and TIA1, are sequestered into the aggregates formed by polyQ-expanded ATXN7 in SCA7 cells. Interestingly, mutant ATXN7 also localises to induced SGs, and this association altered the shape of the SGs. In spite of this, neither the ability to induce nor to disassemble SGs, in response to arsenite stress induction or relief, was affected in SCA7 cells. Moreover, we could not observe any change in the number of ATXN7 aggregates per cell following SG induction, although a small, non-significant, increase in total aggregated ATXN7 material could be detected using filter trap. However, mutant ATXN7 expression in itself increased the speckling of the SG-nucleating protein G3BP1 and the SG response. Taken together, our results indicate that the SG response is induced, and although some key modulators of SGs show altered behaviour, the dynamics of SGs appear normal in the presence of mutant ATXN7.
MeSH term(s)	Ataxin-7/metabolism ; Cytoplasmic Granules/metabolism ; DNA Helicases/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Peptides ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; Spinocerebellar Ataxias/genetics ; Stress Granules ; T-Cell Intracellular Antigen-1/metabolism
Chemical Substances	Ataxin-7 ; DNA-Binding Proteins ; Peptides ; Poly-ADP-Ribose Binding Proteins ; RNA Recognition Motif Proteins ; T-Cell Intracellular Antigen-1 ; TIA1 protein, human ; polyglutamine (26700-71-0) ; DNA Helicases (EC 3.6.4.-) ; G3BP1 protein, human (EC 3.6.4.12) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2022-06-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-02888-2
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Zs.A 2411: Show issues

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Article ; Online: Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair.

Revol, Rebecca S / Koistinen, Niina A / Menon, Preeti K / Chicote-Gonzàlez, Almudena / Iverfeldt, Kerstin / Ström, Anna-Lena

Molecular and cellular neurosciences

2023 Volume 127, Page(s) 103903

Abstract: Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), ... ...

Abstract	Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following β- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different α-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon γ-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) α-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of α-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that α-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.
MeSH term(s)	Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Nuclear Proteins/metabolism ; Carrier Proteins/metabolism ; DNA Repair
Chemical Substances	Amyloid Precursor Protein Secretases (EC 3.4.-) ; Amyloid beta-Protein Precursor ; Nuclear Proteins ; Carrier Proteins
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1046640-x
ISSN	1095-9327 ; 1044-7431
ISSN (online)	1095-9327
ISSN	1044-7431
DOI	10.1016/j.mcn.2023.103903
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Article ; Online: Polyglutamine expanded Ataxin-7 induces DNA damage and alters FUS localization and function.

Niss, Frida / Zaidi, Wajiha / Hallberg, Einar / Ström, Anna-Lena

Molecular and cellular neurosciences

2020 Volume 110, Page(s) 103584

Abstract: Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7 (SCA7), are caused by expansions of polyQ repeats in disease specific proteins. The sequestration of vital proteins into aggregates formed by polyQ proteins is believed to be a common ... ...

Abstract	Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7 (SCA7), are caused by expansions of polyQ repeats in disease specific proteins. The sequestration of vital proteins into aggregates formed by polyQ proteins is believed to be a common pathological mechanism in these disorders. The RNA-binding protein FUS has been observed in polyQ aggregates, though if disruption of this protein plays a role in the neuronal dysfunction in SCA7 or other polyQ diseases remains unclear. We therefore analysed FUS localisation and function in a stable inducible PC12 cell model expressing the SCA7 polyQ protein ATXN7. We found that there was a high degree of FUS sequestration, which was associated with a more cytoplasmic FUS localisation, as well as a decreased expression of FUS regulated mRNAs. In contrast, the role of FUS in the formation of γH2AX positive DNA damage foci was unaffected. In fact, a statistical increase in the number of γH2AX foci, as well as an increased trend of single and double strand DNA breaks, detected by comet assay, could be observed in mutant ATXN7 cells. These results were further corroborated by a clear trend towards increased DNA damage in SCA7 patient fibroblasts. Our findings suggest that both alterations in the RNA regulatory functions of FUS, and increased DNA damage, may contribute to the pathology of SCA7.
MeSH term(s)	Animals ; Ataxin-7/genetics ; Ataxin-7/metabolism ; Cells, Cultured ; DNA Damage ; Fibroblasts/metabolism ; Histones/metabolism ; Humans ; PC12 Cells ; Peptides/chemistry ; Peptides/genetics ; Protein Transport ; RNA-Binding Protein FUS/metabolism ; Rats ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; FUS protein, human ; H2AX protein, human ; Histones ; Peptides ; RNA-Binding Protein FUS ; polyglutamine (26700-71-0)
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1046640-x
ISSN	1095-9327 ; 1044-7431
ISSN (online)	1095-9327
ISSN	1044-7431
DOI	10.1016/j.mcn.2020.103584
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Article ; Online: Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β.

Menon, Preeti Kumaran / Koistinen, Niina Anneli / Iverfeldt, Kerstin / Ström, Anna-Lena

The Journal of biological chemistry

2019 Volume 294, Issue 47, Page(s) 17768–17776

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP ... ...

Abstract	Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP
MeSH term(s)	ADAM10 Protein/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/chemistry ; Amyloid beta-Protein Precursor/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Humans ; Matrix Metalloproteinase Inhibitors/pharmacology ; Metalloendopeptidases/metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Protein Processing, Post-Translational/drug effects
Chemical Substances	Amyloid beta-Protein Precursor ; Matrix Metalloproteinase Inhibitors ; Phosphoserine (17885-08-4) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Metalloendopeptidases (EC 3.4.24.-) ; meprin B (EC 3.4.24.63) ; ADAM10 Protein (EC 3.4.24.81)
Language	English
Publishing date	2019-10-11
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.RA119.008310
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Article ; Online: Monitoring of chromatin organization in live cells by FRIC. Effects of the inner nuclear membrane protein Samp1.

Bergqvist, Cecilia / Niss, Frida / Figueroa, Ricardo A / Beckman, Marie / Maksel, Danuta / Jafferali, Mohammed H / Kulyté, Agné / Ström, Anna-Lena / Hallberg, Einar

Nucleic acids research

2019 Volume 47, Issue 9, Page(s) e49

Abstract: In most cells, transcriptionally inactive heterochromatin is preferentially localized in the nuclear periphery and transcriptionally active euchromatin is localized in the nuclear interior. Different cell types display characteristic chromatin ... ...

Abstract	In most cells, transcriptionally inactive heterochromatin is preferentially localized in the nuclear periphery and transcriptionally active euchromatin is localized in the nuclear interior. Different cell types display characteristic chromatin distribution patterns, which change dramatically during cell differentiation, proliferation, senescence and different pathological conditions. Chromatin organization has been extensively studied on a cell population level, but there is a need to understand dynamic reorganization of chromatin at the single cell level, especially in live cells. We have developed a novel image analysis tool that we term Fluorescence Ratiometric Imaging of Chromatin (FRIC) to quantitatively monitor dynamic spatiotemporal distribution of euchromatin and total chromatin in live cells. A vector (pTandemH) assures stoichiometrically constant expression of the histone variants Histone 3.3 and Histone 2B, fused to EGFP and mCherry, respectively. Quantitative ratiometric (H3.3/H2B) imaging displayed a concentrated distribution of heterochromatin in the periphery of U2OS cell nuclei. As proof of concept, peripheral heterochromatin responded to experimental manipulation of histone acetylation. We also found that peripheral heterochromatin depended on the levels of the inner nuclear membrane protein Samp1, suggesting an important role in promoting peripheral heterochromatin. Taken together, FRIC is a powerful and robust new tool to study dynamic chromatin redistribution in live cells.
MeSH term(s)	Acetylation ; Cell Line ; Cell Nucleus/genetics ; Chromatin/genetics ; Euchromatin/genetics ; Heterochromatin/genetics ; Histones/genetics ; Humans ; Membrane Proteins/genetics ; Molecular Imaging/methods ; Nuclear Envelope/genetics ; Nuclear Proteins/genetics ; Protein Processing, Post-Translational/genetics
Chemical Substances	Chromatin ; Euchromatin ; Heterochromatin ; Histones ; Membrane Proteins ; Nuclear Proteins ; TMEM201 protein, human
Language	English
Publishing date	2019-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkz123
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Zs.A 1067: Show issues

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Article: Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model.

Ajayi, Abiodun / Yu, Xin / Wahlo-Svedin, Carolina / Tsirigotaki, Galateia / Karlström, Victor / Ström, Anna-Lena

Biochimica et biophysica acta

2015 Volume 1847, Issue 4-5, Page(s) 418–428

Abstract: Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. ... ...

Abstract	Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. However, the exact molecular mechanism(s) behind the metabolic dysfunction is still unclear. In this study we identified a previously unreported mechanism, involving disruption of p53 and NADPH oxidase 1 (NOX1) activity, by which the expanded SCA7 disease protein ATXN7 causes metabolic dysregulation. The NOX1 protein is known to promote glycolytic activity, whereas the transcription factor p53 inhibits this process and instead promotes mitochondrial respiration. In a stable inducible PC12 model of SCA7, p53 and mutant ATXN7 co-aggregated and the transcriptional activity of p53 was reduced, resulting in a 50% decrease of key p53 target proteins, like AIF and TIGAR. In contrast, the expression of NOX1 was increased approximately 2 times in SCA7 cells. Together these alterations resulted in a decreased respiratory capacity, an increased reliance on glycolysis for energy production and a subsequent 20% reduction of ATP in SCA7 cells. Restoring p53 function, or suppressing NOX1 activity, both reversed the metabolic dysfunction and ameliorated mutant ATXN7 toxicity. These results hence not only enhance the understanding of the mechanisms causing metabolic dysfunction in SCA7 disease, but also identify NOX1 as a novel potential therapeutic target in SCA7 and possibly other polyQ diseases.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Apoptosis Inducing Factor/genetics ; Apoptosis Inducing Factor/metabolism ; Apoptosis Regulatory Proteins ; Ataxin-7 ; Blotting, Western ; Disease Models, Animal ; Energy Metabolism ; Glucose ; Glucose Transporter Type 1/genetics ; Glucose Transporter Type 1/metabolism ; HeLa Cells ; Humans ; Immunoenzyme Techniques ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lactic Acid ; Membrane Potential, Mitochondrial ; Mutation/genetics ; NADH, NADPH Oxidoreductases/genetics ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase 1 ; Nerve Tissue Proteins/deficiency ; Oxygen Consumption ; PC12 Cells ; Peptides/genetics ; RNA, Messenger/genetics ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	AIFM1 protein, human ; ATXN7 protein, human ; Apoptosis Inducing Factor ; Apoptosis Regulatory Proteins ; Ataxin-7 ; Atxn7 protein, rat ; Glucose Transporter Type 1 ; Intracellular Signaling Peptides and Proteins ; Nerve Tissue Proteins ; Peptides ; RNA, Messenger ; Tumor Suppressor Protein p53 ; polyglutamine (26700-71-0) ; Lactic Acid (33X04XA5AT) ; Adenosine Triphosphate (8L70Q75FXE) ; NADH, NADPH Oxidoreductases (EC 1.6.-) ; NADPH Oxidase 1 (EC 1.6.3.-) ; NOX1 protein, rat (EC 1.6.3.-) ; TIGAR protein, human (EC 3.1.3.2) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2015-01-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbabio.2015.01.012
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Article ; Online: Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model.

Yu, Xin / Ajayi, Abiodun / Boga, Narasimha Rao / Ström, Anna-Lena

Journal of molecular neuroscience : MN

2012 Volume 47, Issue 2, Page(s) 219–233

Abstract: Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats, and a common toxic gain-of-function mechanism has been proposed. Proteolytic cleavage of several polyglutamine proteins has been ... ...

Abstract	Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats, and a common toxic gain-of-function mechanism has been proposed. Proteolytic cleavage of several polyglutamine proteins has been identified and suggested to modulate the polyglutamine toxicity. In this study, we show that full-length and cleaved fragments of the SCA7 disease protein ataxin-7 (ATXN7) are differentially degraded. We found that the ubiquitin-proteosome system (UPS) was essential for the degradation of full-length endogenous ATXN7 or transgenic full-length ATXN7 with a normal or expanded glutamine repeat in both HEK 293T and stable PC12 cells. However, a similar contribution by UPS and autophagy was found for the degradation of proteolytically cleaved ATXN7 fragments. Furthermore, in our novel stable inducible PC12 model, induction of mutant ATXN7 expression resulted in toxicity and this toxicity was worsened by inhibition of either UPS or autophagy. In contrast, pharmacological activation of autophagy could ameliorate the ATXN7-induced toxicity. Based on our findings, we propose that both UPS and autophagy are important for the reduction of mutant ataxin-7-induced toxicity, and enhancing ATXN7 clearance through autophagy could be used as a potential therapeutic strategy in SCA7.
MeSH term(s)	Animals ; Ataxin-7 ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; HEK293 Cells ; Humans ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; PC12 Cells ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Peptides/genetics ; Peptides/metabolism ; Rats ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism ; Transgenes/physiology
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; Atxn7 protein, rat ; Nerve Tissue Proteins ; Peptide Fragments ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2012-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1043392-2
ISSN	1559-1166 ; 0895-8696
ISSN (online)	1559-1166
ISSN	0895-8696
DOI	10.1007/s12031-012-9722-8
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Zs.A 3006: Show issues

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Article ; Online: Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model

Ajayi Abiodun / Yu Xin / Lindberg Staffan / Langel Ülo / Ström Anna-Lena

BMC Neuroscience, Vol 13, Iss 1, p

2012 Volume 86

Abstract: Abstract Background Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the ... ...

Abstract	Abstract Background Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear. Results In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Conclusion Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.
Keywords	Ataxin-7 ; NADPH oxidase complex ; Neurodegeneration ; Oxidative stress ; Polyglutamine ; SCA7 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	500
Language	English
Publishing date	2012-07-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport.

Shi, Ping / Ström, Anna-Lena / Gal, Jozsef / Zhu, Haining

Biochimica et biophysica acta

2010 Volume 1802, Issue 9, Page(s) 707–716

Abstract: Transport of material and signals between extensive neuronal processes and the cell body is essential to neuronal physiology and survival. Slowing of axonal transport has been shown to occur before the onset of symptoms in amyotrophic lateral sclerosis ( ... ...

Abstract	Transport of material and signals between extensive neuronal processes and the cell body is essential to neuronal physiology and survival. Slowing of axonal transport has been shown to occur before the onset of symptoms in amyotrophic lateral sclerosis (ALS). We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interacted and colocalized with the retrograde dynein-dynactin motor complex in cultured cells and affected tissues of ALS mice. We also found that the interaction between mutant SOD1 and the dynein motor played a critical role in the formation of large inclusions containing mutant SOD1. In this study, we showed that, in contrast to the dynein situation, mutant SOD1 did not interact with anterograde transport motors of the kinesin-1 family (KIF5A, B and C). Using dynein and kinesin accumulation at the sciatic nerve ligation sites as a surrogate measurement of axonal transport, we also showed that dynein mediated retrograde transport was slower in G93A than in WT mice at an early presymptomatic stage. While no decrease in KIF5A-mediated anterograde transport was detected, the slowing of anterograde transport of dynein heavy chain as a cargo was observed in the presymptomatic G93A mice. The results from this study along with other recently published work support that mutant SOD1 might only interact with and interfere with some kinesin members, which, in turn, could result in the impairment of a selective subset of cargos. Although it remains to be further investigated how mutant SOD1 affects different axonal transport motor proteins and various cargos, it is evident that mutant SOD1 can induce defects in axonal transport, which, subsequently, contribute to the propagation of toxic effects and ultimately motor neuron death in ALS.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Animals ; Axonal Transport/genetics ; Axonal Transport/physiology ; Cells, Cultured ; Disease Models, Animal ; Dyneins/metabolism ; Dyneins/physiology ; Humans ; Kinesins/metabolism ; Kinesins/physiology ; Mice ; Mice, Transgenic ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Models, Biological ; Motor Neurons/metabolism ; Motor Neurons/physiology ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutant Proteins/physiology ; Protein Binding/genetics ; Protein Binding/physiology ; Protein Transport/genetics ; Protein Transport/physiology ; Superoxide Dismutase/genetics ; Superoxide Dismutase/physiology
Chemical Substances	Kif5A protein, mouse ; Microtubule-Associated Proteins ; Mutant Proteins ; Superoxide Dismutase (EC 1.15.1.1) ; Kif5b protein, mouse (EC 3.6.1.-) ; Dyneins (EC 3.6.4.2) ; Kinesins (EC 3.6.4.4)
Language	English
Publishing date	2010-05-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2010.05.008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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