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Article ; Online: Reply to: "Comment on: Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood".

Hübener-Schmid, Jeannette / Kuhlbrodt, Kirsten / Peladan, Julien / Rieß, Olaf

Movement disorders : official journal of the Movement Disorder Society

2022 Volume 37, Issue 5, Page(s) 1121–1122

MeSH term(s)	Ataxin-3/genetics ; Humans ; Machado-Joseph Disease/genetics ; Nuclear Proteins ; Peptides
Chemical Substances	Nuclear Proteins ; Peptides ; polyglutamine (26700-71-0) ; Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2022-05-19
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.29003
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Zs.A 2555: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 238: Show issues

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Book ; Thesis: Die Rolle von Sox-Proteinen bei der Gliazelldifferenzierung von Rattus norvegicus (Berkenhout) und ihre Relevanz bei Entwicklungsstörungen des Menschen

Kuhlbrodt, Kirsten

1999

Author's details	vorgelegt von Kirsten Kuhlbrodt
Language	German
Size	Ill., graph. Darst
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., FB Biologie, Diss.--Hamburg, 1999
Note	Enthält: 5 Zeitschriftenaufsätze
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model.

Marchionini, Deanna M / Liu, Jeh-Ping / Ambesi-Impiombato, Alberto / Kerker, Kimberly / Cirillo, Kim / Bansal, Mukesh / Mushlin, Rich / Brunner, Daniela / Ramboz, Sylvie / Kwan, Mei / Kuhlbrodt, Kirsten / Tillack, Karsten / Peters, Finn / Rauhala, Leena / Obenauer, John / Greene, Jonathan R / Hartl, Christopher / Khetarpal, Vinod / Lager, Brenda /

Rosinski, Jim / Aaronson, Jeff / Alam, Morshed / Signer, Ethan / Muñoz-Sanjuán, Ignacio / Howland, David / Zeitlin, Scott O

JCI insight

2022 Volume 7, Issue 20

Abstract: We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term ... ...

Abstract	We have developed an inducible Huntington's disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all mHtt-lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late mHtt lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefits in humans.
MeSH term(s)	Mice ; Humans ; Animals ; Infant ; Huntington Disease/drug therapy ; Huntington Disease/genetics ; Protein Aggregates ; Huntingtin Protein/genetics ; Huntingtin Protein/cerebrospinal fluid ; Disease Models, Animal ; Corpus Striatum/metabolism ; Disease Progression
Chemical Substances	Protein Aggregates ; Huntingtin Protein
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.161769
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Article ; Online: Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

Hübener-Schmid, Jeannette / Kuhlbrodt, Kirsten / Peladan, Julien / Faber, Jennifer / Santana, Magda M / Hengel, Holger / Jacobi, Heike / Reetz, Kathrin / Garcia-Moreno, Hector / Raposo, Mafalda / van Gaalen, Judith / Infante, Jon / Steiner, Katharina M / de Vries, Jeroen / Verbeek, Marcel M / Giunti, Paola / Pereira de Almeida, Luis / Lima, Manuela / van de Warrenburg, Bart /

Schöls, Ludger / Klockgether, Thomas / Synofzik, Matthis / Riess, Olaf

Movement disorders : official journal of the Movement Disorder Society

2021 Volume 36, Issue 11, Page(s) 2675–2681

Abstract: Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) ... ...

Abstract	Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
MeSH term(s)	Ataxin-3/genetics ; Cross-Sectional Studies ; Humans ; Machado-Joseph Disease/drug therapy ; Machado-Joseph Disease/genetics ; Neurodegenerative Diseases ; Peptides
Chemical Substances	Peptides ; polyglutamine (26700-71-0) ; Ataxin-3 (EC 3.4.19.12)
Language	English
Publishing date	2021-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.28749
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Zs.MO 238: Show issues

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Article ; Online: Quantifying autophagy using novel LC3B and p62 TR-FRET assays.

Bresciani, Alberto / Spiezia, Maria Carolina / Boggio, Roberto / Cariulo, Cristina / Nordheim, Anja / Altobelli, Roberta / Kuhlbrodt, Kirsten / Dominguez, Celia / Munoz-Sanjuan, Ignacio / Wityak, John / Fodale, Valentina / Marchionini, Deanna M / Weiss, Andreas

PloS one

2018 Volume 13, Issue 3, Page(s) e0194423

Abstract: Autophagy is a cellular mechanism that can generate energy for cells or clear misfolded or aggregated proteins, and upregulating this process has been proposed as a therapeutic approach for neurodegenerative diseases. Here we describe a novel set of LC3B- ...

Abstract	Autophagy is a cellular mechanism that can generate energy for cells or clear misfolded or aggregated proteins, and upregulating this process has been proposed as a therapeutic approach for neurodegenerative diseases. Here we describe a novel set of LC3B-II and p62 time-resolved fluorescence resonance energy transfer (TR-FRET) assays that can detect changes in autophagy in the absence of exogenous labels. Lipidated LC3 is a marker of autophagosomes, while p62 is a substrate of autophagy. These assays can be employed in high-throughput screens to identify novel autophagy upregulators, and can measure autophagy changes in cultured cells or tissues after genetic or pharmacological interventions. We also demonstrate that different cells exhibit varying autophagic responses to pharmacological interventions. Overall, it is clear that a battery of readouts is required to make conclusions about changes in autophagy.
MeSH term(s)	Animals ; Autophagosomes/metabolism ; Autophagy/physiology ; Fluorescence Resonance Energy Transfer/methods ; HEK293 Cells ; Humans ; Microtubule-Associated Proteins/metabolism ; Rats ; Sequestosome-1 Protein/metabolism
Chemical Substances	LC3 protein, rat ; Microtubule-Associated Proteins ; Sequestosome-1 Protein ; Sqstm1 protein, rat
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0194423
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Article ; Online: The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis.

Kuhlbrodt, Kirsten / Janiesch, Philipp Christoph / Kevei, Éva / Segref, Alexandra / Barikbin, Roja / Hoppe, Thorsten

Nature cell biology

2011 Volume 13, Issue 3, Page(s) 273–281

Abstract: Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently ...

Abstract	Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and deubiquitylation. A conserved factor that orchestrates distinct substrate-processing co-regulators in diverse species is the ubiquitin-selective chaperone CDC-48 (also known as p97). Several deubiquitylation enzymes (DUBs) have been shown to interact with CDC-48/p97, but the mechanistic and physiological relevance of these interactions remained elusive. Here we report a synergistic cooperation between CDC-48 and ATX-3 (the Caenorhabditis elegans orthologue of ataxin-3) in ubiquitin-mediated proteolysis and ageing regulation. Surprisingly, worms deficient for both cdc-48.1 and atx-3 demonstrated extended lifespan by up to 50%, mediated through the insulin-insulin-like growth factor 1 (IGF-1) signalling pathway. As lifespan extension specifically depends on the deubiquitylation activity of ATX-3, our findings identify a mechanistic link between protein degradation and longevity through editing of the ubiquitylation status of substrates involved in insulin-IGF-1 signalling.
MeSH term(s)	Adenosine Triphosphatases/metabolism ; Animals ; Ataxin-3 ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Endoplasmic Reticulum/metabolism ; Gene Expression Regulation ; Humans ; Insulin/metabolism ; Longevity ; Machado-Joseph Disease/metabolism ; Models, Biological ; Mutation ; Nerve Tissue Proteins/metabolism ; Signal Transduction ; Time Factors ; Two-Hybrid System Techniques ; Ubiquitin/metabolism ; Valosin Containing Protein
Chemical Substances	Caenorhabditis elegans Proteins ; Cell Cycle Proteins ; Insulin ; Nerve Tissue Proteins ; Ubiquitin ; Ataxin-3 (EC 3.4.19.12) ; atx-3 protein, C elegans (EC 3.4.19.12) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2011-02-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb2200
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Article: Orchestra for assembly and fate of polyubiquitin chains.

Kuhlbrodt, Kirsten / Mouysset, Julien / Hoppe, Thorsten

Essays in biochemistry

2005 Volume 41, Page(s) 1–14

Abstract: Selective protein degradation by the 26 S proteasome usually requires a polyubiquitin chain attached to the protein substrate by three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) ...

Abstract	Selective protein degradation by the 26 S proteasome usually requires a polyubiquitin chain attached to the protein substrate by three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). This reaction can produce different polyubiquitin chains that, depending on size and linkage type, can provide distinct intracellular signals. Interestingly, polyubiquitination is sometimes regulated by additional conjugation factors, called E4s (polyubiquitin chain conjugation factors). Yeast UFD2 (ubiquitin fusion degradation protein-2), the first E4 to be described, binds to the ubiquitin moieties of preformed conjugates and catalyses ubiquitin-chain elongation together with E1, E2, and E3. Recent studies have illustrated that the E4 enzyme UFD2 co-operates with an orchestra of ubiquitin-binding factors in an escort pathway to transfer and deliver polyubiquitinated substrates to the 26 S proteasome. Here we propose a model in which E4-dependent polyubiquitination pathways are modulated by different ubiquitin-binding proteins, using ataxin-3 as an example.
MeSH term(s)	Animals ; Ataxin-3 ; Humans ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins ; Polyubiquitin/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Repressor Proteins ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin-Activating Enzymes/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Nerve Tissue Proteins ; Nuclear Proteins ; Repressor Proteins ; Saccharomyces cerevisiae Proteins ; Polyubiquitin (120904-94-1) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; ATXN3 protein, human (EC 3.4.19.12) ; Ataxin-3 (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-) ; Ubiquitin-Activating Enzymes (EC 6.2.1.45) ; UFD2 protein, S cerevisiae (EC 6.3.2.-)
Language	English
Publishing date	2005
Publishing country	England
Document type	Journal Article ; Review
ISSN	0071-1365
ISSN	0071-1365
DOI	10.1042/EB0410001
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Article: NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas.

Henseleit, Korinna D / Nelson, Shelley B / Kuhlbrodt, Kirsten / Hennings, J Christopher / Ericson, Johan / Sander, Maike

Development (Cambridge, England)

2005 Volume 132, Issue 13, Page(s) 3139–3149

Abstract: In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting beta-cells of the pancreatic islets. As successful generation of insulin-producing cells in vitro could constitute a cure for diabetes, ... ...

Abstract	In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting beta-cells of the pancreatic islets. As successful generation of insulin-producing cells in vitro could constitute a cure for diabetes, recent studies have explored the molecular program that underlies beta-cell formation. From these studies, the homeodomain transcription factor NKX6.1 has proven to be a key player. In Nkx6.1 mutants, beta-cell numbers are selectively reduced, while other islet cell types develop normally. However, the molecular events downstream of NKX6.1, as well as the molecular pathways that ensure residual beta-cell formation in the absence of NKX6.1 are largely unknown. Here, we show that the Nkx6.1 paralog, Nkx6.2, is expressed during pancreas development and partially compensates for NKX6.1 function. Surprisingly, our analysis of Nkx6 compound mutant mice revealed a previously unrecognized requirement for NKX6 activity in alpha-cell formation. This finding suggests a more general role for NKX6 factors in endocrine cell differentiation than formerly suggested. Similar to NKX6 factors, the transcription factor MYT1 has recently been shown to regulate alpha- as well as beta-cell development. We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cell Differentiation/physiology ; DNA-Binding Proteins/biosynthesis ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Developmental/physiology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/physiology ; Mice ; Mutation ; Nerve Tissue Proteins/metabolism ; Pancreas/embryology ; Transcription Factors/biosynthesis ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; DNA-Binding Proteins ; Homeodomain Proteins ; Myt1 protein, mouse ; Nerve Tissue Proteins ; Neurog3 protein, mouse ; Nkx6-1 protein, mouse ; Nkx6.2 protein, vertebrate ; Transcription Factors
Language	English
Publishing date	2005-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.01875
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