LIVIVO - Search results -

Search results

Result 1 - 10 of total 21

Search options

Article ; Online: RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia.

McMillan, Michael / Gomez, Nicolas / Hsieh, Caroline / Bekier, Michael / Li, Xingli / Miguez, Roberto / Tank, Elizabeth M H / Barmada, Sami J

Molecular cell

2023 Volume 83, Issue 2, Page(s) 219–236.e7

Abstract: RNA methylation at adenosine N6 (m6A) is one of the most common RNA modifications, impacting RNA stability, transport, and translation. Previous studies uncovered RNA destabilization in amyotrophic lateral sclerosis (ALS) models in association with ... ...

Abstract	RNA methylation at adenosine N6 (m6A) is one of the most common RNA modifications, impacting RNA stability, transport, and translation. Previous studies uncovered RNA destabilization in amyotrophic lateral sclerosis (ALS) models in association with accumulation of the RNA-binding protein TDP43. Here, we show that TDP43 recognizes m6A RNA and that RNA methylation is critical for both TDP43 binding and autoregulation. We also observed extensive RNA hypermethylation in ALS spinal cord, corresponding to methylated TDP43 substrates. Emphasizing the importance of m6A for TDP43 binding and function, we identified several m6A factors that enhance or suppress TDP43-mediated toxicity via single-cell CRISPR-Cas9 in primary neurons. The most promising modifier-the canonical m6A reader YTHDF2-accumulated within ALS spinal neurons, and its knockdown prolonged the survival of human neurons carrying ALS-associated mutations. Collectively, these data show that m6A modifications modulate RNA binding by TDP43 and that m6A is pivotal for TDP43-related neurodegeneration in ALS.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/pathology ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Methylation ; Neurons/metabolism ; RNA/genetics ; RNA/metabolism
Chemical Substances	RNA (63231-63-0) ; TARDBP protein, human
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.12.019
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 5055: 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)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾

Article ; Online: RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

McMillan, Michael / Gómez, Nicolás / Hsieh, Caroline / Bekier, Michael / Li, Xingli / Míguez, Roberto / Tank, Elizabeth M.H. / Barmada, Sami J.

Molecular Cell. 2023 Jan., v. 83, no. 2 p.219-236.e7

2023

Abstract	RNA methylation at adenosine N6 (m6A) is one of the most common RNA modifications, impacting RNA stability, transport, and translation. Previous studies uncovered RNA destabilization in amyotrophic lateral sclerosis (ALS) models in association with accumulation of the RNA-binding protein TDP43. Here, we show that TDP43 recognizes m6A RNA and that RNA methylation is critical for both TDP43 binding and autoregulation. We also observed extensive RNA hypermethylation in ALS spinal cord, corresponding to methylated TDP43 substrates. Emphasizing the importance of m6A for TDP43 binding and function, we identified several m6A factors that enhance or suppress TDP43-mediated toxicity via single-cell CRISPR-Cas9 in primary neurons. The most promising modifier—the canonical m6A reader YTHDF2—accumulated within ALS spinal neurons, and its knockdown prolonged the survival of human neurons carrying ALS-associated mutations. Collectively, these data show that m6A modifications modulate RNA binding by TDP43 and that m6A is pivotal for TDP43-related neurodegeneration in ALS.
Keywords	CRISPR-Cas systems ; RNA ; RNA-binding proteins ; adenosine ; amyotrophic lateral sclerosis ; autoregulation ; dementia ; humans ; methylation ; pathogenesis ; spinal cord ; toxicity ; m6A ; TDP43 ; ALS ; RNA modifications ; neurodegeneration
Language	English
Dates of publication	2023-01
Size	p. 219-236.e7.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.12.019
Database	NAL-Catalogue (AGRICOLA)

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Bonn / Germany

Z 2005/501: Show issues

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾

Article ; Online: Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.

Tseng, Yi-Ju / Krans, Amy / Malik, Indranil / Deng, Xiexiong / Yildirim, Evrim / Ovunc, Sinem / Tank, Elizabeth M H / Jansen-West, Karen / Kaufhold, Ross / Gomez, Nicolas B / Sher, Roger / Petrucelli, Leonard / Barmada, Sami J / Todd, Peter K

Nucleic acids research

2024

Abstract: A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated ... ...

Abstract	A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation-suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.
Language	English
Publishing date	2024-02-27
Publishing country	England
Document type	Journal Article
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/gkae137
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1067: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Development of a specific live-cell assay for native autophagic flux.

Safren, Nathaniel / Tank, Elizabeth M / Malik, Ahmed M / Chua, Jason P / Santoro, Nicholas / Barmada, Sami J

The Journal of biological chemistry

2021 Volume 297, Issue 3, Page(s) 101003

Abstract: Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating ... ...

Abstract	Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. We used this assay to perform high-throughput drug screens of four chemical libraries comprising over 30,000 diverse compounds, identifying several clinically relevant drugs and novel autophagy modulators. A select series of candidate compounds also modulated autophagy flux in human motor neurons modified by CRISPR/Cas9 to express GFP-labeled LC3. Using automated microscopy, we tested the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In doing so, we found that autophagy induction exhibited discordant effects, improving survival in disease models involving the RNA binding protein TDP-43, while exacerbating toxicity in neurons expressing mutant forms of UBQLN2 and C9ORF72 associated with familial ALS/FTD. These studies confirm the utility of the Dendra2-LC3 assay, while illustrating the contradictory effects of autophagy induction in different ALS/FTD subtypes.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/therapy ; Autophagy/drug effects ; Autophagy-Related Proteins/genetics ; C9orf72 Protein/genetics ; CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; Drug Screening Assays, Antitumor ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/therapy ; HEK293 Cells ; High-Throughput Screening Assays ; Humans ; Luminescent Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Models, Biological ; Motor Neurons/metabolism ; Mutation
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; Dendra2 protein, Dendronephthya ; Luminescent Proteins ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; TARDBP protein, human ; UBQLN2 protein, human
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101003
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Uc I Zs.108: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Enhanced detection of expanded repeat mRNA foci with hybridization chain reaction.

Glineburg, M Rebecca / Zhang, Yuan / Krans, Amy / Tank, Elizabeth M / Barmada, Sami J / Todd, Peter K

Acta neuropathologica communications

2021 Volume 9, Issue 1, Page(s) 73

Abstract: Transcribed nucleotide repeat expansions form detectable RNA foci in patient cells that contribute to disease pathogenesis. The most widely used method for detecting RNA foci, fluorescence in situ hybridization (FISH), is powerful but can suffer from ... ...

Abstract	Transcribed nucleotide repeat expansions form detectable RNA foci in patient cells that contribute to disease pathogenesis. The most widely used method for detecting RNA foci, fluorescence in situ hybridization (FISH), is powerful but can suffer from issues related to signal above background. Here we developed a repeat-specific form of hybridization chain reaction (R-HCR) as an alternative method for detection of repeat RNA foci in two neurodegenerative disorders: C9orf72 associated ALS and frontotemporal dementia (C9 ALS/FTD) and Fragile X-associated tremor/ataxia syndrome. R-HCR to both G
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism ; Cells, Cultured ; DNA Repeat Expansion/physiology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Frontotemporal Dementia/pathology ; Humans ; In Situ Hybridization, Fluorescence/methods ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	C9orf72 Protein ; C9orf72 protein, human ; RNA, Messenger
Language	English
Publishing date	2021-04-23
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, Non-P.H.S.
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-021-01169-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article: Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.

Tseng, Yi-Ju / Malik, Indranil / Deng, Xiexiong / Krans, Amy / Jansen-West, Karen / Tank, Elizabeth M H / Gomez, Nicolas B / Sher, Roger / Petrucelli, Leonard / Barmada, Sami J / Todd, Peter K

bioRxiv : the preprint server for biology

2023

Abstract: A GGGGCC (G4C2) hexanucleotide repeat expansion ... ...

Abstract	A GGGGCC (G4C2) hexanucleotide repeat expansion in
Language	English
Publishing date	2023-06-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.07.544135
Database	MEDical Literature Analysis and Retrieval System OnLINE

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾

Article ; Online: Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons.

Chua, Jason P / Bedi, Karan / Paulsen, Michelle T / Ljungman, Mats / Tank, Elizabeth M H / Kim, Erin S / McBride, Jonathon P / Colón-Mercado, Jennifer M / Ward, Michael E / Weisman, Lois S / Barmada, Sami J

Current biology : CB

2022 Volume 32, Issue 12, Page(s) 2581–2595.e6

Abstract: Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the ...

Abstract	Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs), and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not the unrelated phosphatase MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Our findings thus establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell-type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.
MeSH term(s)	Autophagosomes/metabolism ; Autophagy/genetics ; Neurons/physiology ; Protein Tyrosine Phosphatases, Non-Receptor/genetics ; Protein Tyrosine Phosphatases, Non-Receptor/metabolism
Chemical Substances	Protein Tyrosine Phosphatases, Non-Receptor (EC 3.1.3.48) ; myotubularin (EC 3.1.3.48)
Language	English
Publishing date	2022-05-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2022.04.053
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 3208: 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)

Order via subito

Details ▾

Article ; Online: Spontaneous age-related neurite branching in Caenorhabditis elegans.

Tank, Elizabeth M H / Rodgers, Kasey E / Kenyon, Cynthia

The Journal of neuroscience : the official journal of the Society for Neuroscience

2011 Volume 31, Issue 25, Page(s) 9279–9288

Abstract: The analysis of morphological changes that occur in the nervous system during normal aging could provide insight into cognitive decline and neurodegenerative disease. Previous studies have suggested that the nervous system of Caenorhabditis elegans ... ...

Abstract	The analysis of morphological changes that occur in the nervous system during normal aging could provide insight into cognitive decline and neurodegenerative disease. Previous studies have suggested that the nervous system of Caenorhabditis elegans maintains its structural integrity with age despite the deterioration of surrounding tissues. Unexpectedly, we observed that neurons in aging animals frequently displayed ectopic branches and that the prevalence of these branches increased with time. Within age-matched populations, the branching of mechanosensory neurons correlated with decreased response to light touch and decreased mobility. The incidence of branching was influenced by two pathways that can affect the rate of aging, the Jun kinase pathway and the insulin/IGF-1 pathway. Loss of Jun kinase signaling, which slightly shortens lifespan, dramatically increased and accelerated the frequency of neurite branching. Conversely, inhibition of the daf-2 insulin/IGF-1-like signaling pathway, which extends lifespan, delayed and suppressed branching, and this delay required DAF-16/FOXO activity. Both JNK-1 and DAF-16 appeared to act within neurons in a cell-autonomous manner to influence branching, and, through their tissue-specific expression, it was possible to disconnect the rate at which branching occurred from the overall rate of aging of the animal. Old age has generally been associated with the decline and deterioration of different tissues, except in the case of tumor cell growth. To our knowledge, this is the first indication that aging can potentiate another form of growth, the growth of neurite branches, in normal animals.
MeSH term(s)	Aging/physiology ; Animals ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/growth & development ; Cell Enlargement ; Cells, Cultured ; Morphogenesis/physiology ; Neurites/physiology ; Neurites/ultrastructure
Language	English
Publishing date	2011-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.6606-10.2011
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1668: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.

Weskamp, Kaitlin / Tank, Elizabeth M / Miguez, Roberto / McBride, Jonathon P / Gómez, Nicolás B / White, Matthew / Lin, Ziqiang / Gonzalez, Carmen Moreno / Serio, Andrea / Sreedharan, Jemeen / Barmada, Sami J

The Journal of clinical investigation

2019 Volume 130, Issue 3, Page(s) 1139–1155

Abstract: Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that ... ...

Abstract	Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Line ; DNA-Binding Proteins/biosynthesis ; DNA-Binding Proteins/genetics ; Humans ; Mice ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Neuroglia/metabolism ; Neuroglia/pathology ; Protein Isoforms/biosynthesis ; Protein Isoforms/genetics
Chemical Substances	DNA-Binding Proteins ; Protein Isoforms ; TARDBP protein, human
Language	English
Publishing date	2019-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI130988
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Ua VI Zs.184: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates.

Tank, Elizabeth M H / True, Heather L

PLoS genetics

2009 Volume 5, Issue 2, Page(s) e1000382

Abstract: Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of ...

Abstract	Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ub(ext)) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ub(ext) or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ub(ext) altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ub(ext) markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ub(ext) interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amino Acid Sequence ; Base Sequence ; Frameshift Mutation ; Humans ; Molecular Sequence Data ; Peptide Termination Factors ; Peptides/metabolism ; Prions/metabolism ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin/genetics ; Ubiquitin/metabolism ; Ubiquitination
Chemical Substances	Peptide Termination Factors ; Peptides ; Prions ; Proteins ; SUP35 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Ubiquitin ; polyglutamine (26700-71-0) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2009-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1000382
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

To top

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Bonn / Germany

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Inter-library loan at ZB MED

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito