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Article ; Online: A cause for childhood ataxia.

Steffan, Joan S

2016 Volume 5

Abstract: Genetic studies uncover a mutation in a widely conserved protein as the cause of a neurological disorder in two brothers. ...

Abstract	Genetic studies uncover a mutation in a widely conserved protein as the cause of a neurological disorder in two brothers.
MeSH term(s)	Ataxia ; Humans ; Mutation ; Proteins/genetics
Chemical Substances	Proteins
Language	English
Publishing date	2016-03-01
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.14523
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Article ; Online: Cooperation of cell adhesion and autophagy in the brain: Functional roles in development and neurodegenerative disease.

Hernandez, Sarah J / Fote, Gianna / Reyes-Ortiz, Andrea M / Steffan, Joan S / Thompson, Leslie M

Matrix biology plus

2021 Volume 12, Page(s) 100089

Abstract: Cellular adhesive connections directed by the extracellular matrix (ECM) and maintenance of cellular homeostasis by autophagy are seemingly disparate functions that are molecularly intertwined, each regulating the other. This is an emerging field in the ... ...

Abstract	Cellular adhesive connections directed by the extracellular matrix (ECM) and maintenance of cellular homeostasis by autophagy are seemingly disparate functions that are molecularly intertwined, each regulating the other. This is an emerging field in the brain where the interplay between adhesion and autophagy functions at the intersection of neuroprotection and neurodegeneration. The ECM and adhesion proteins regulate autophagic responses to direct protein clearance and guide regenerative programs that go awry in brain disorders. Concomitantly, autophagic flux acts to regulate adhesion dynamics to mediate neurite outgrowth and synaptic plasticity with functional disruption contributed by neurodegenerative disease. This review highlights the cooperative exchange between cellular adhesion and autophagy in the brain during health and disease. As the mechanistic alliance between adhesion and autophagy has been leveraged therapeutically for metastatic disease, understanding overlapping molecular functions that direct the interplay between adhesion and autophagy might uncover therapeutic strategies to correct or compensate for neurodegeneration.
Language	English
Publishing date	2021-10-23
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	2590-0285
ISSN (online)	2590-0285
DOI	10.1016/j.mbplus.2021.100089
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Article ; Online: Does Huntingtin play a role in selective macroautophagy?

Steffan, Joan S

Cell cycle (Georgetown, Tex.)

2010 Volume 9, Issue 17, Page(s) 3401–3413

Abstract: The accumulation of protein aggregates in neurons appears to be a basic feature of neurodegenerative disease. In Huntington's Disease (HD), a progressive and ultimately fatal neurodegenerative disorder caused by an expansion of the polyglutamine repeat ... ...

Abstract	The accumulation of protein aggregates in neurons appears to be a basic feature of neurodegenerative disease. In Huntington's Disease (HD), a progressive and ultimately fatal neurodegenerative disorder caused by an expansion of the polyglutamine repeat within the protein Huntingtin (Htt), the immediate proximal cause of disease is well understood. However, the cellular mechanisms which modulate the rate at which fragments of Htt containing polyglutamine accumulate in neurons is a central issue in the development of approaches to modulate the rate and extent of neuronal loss in this disease. We have recently found that Htt is phosphorylated by the kinase IKK on serine (S) 13, activating its phosphorylation on S16 and its acetylation and poly-SUMOylation, modifications that modulate its clearance by the proteasome and lysosome in cells. In the discussion here I suggest that Htt may have a normal function in the lysosomal mechanism of selective macroautophagy involved in its own degradation which may share some similarity with the yeast cytoplasm to vacuole targeting (Cvt) pathway. Pharmacologic activation of this pathway may be useful early in disease progression to treat HD and other neurodegenerative diseases characterized by the accumulation of disease proteins.
MeSH term(s)	Autophagy ; Humans ; Huntingtin Protein ; Huntington Disease/metabolism ; I-kappa B Kinase/metabolism ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/physiology ; Nuclear Proteins/metabolism ; Nuclear Proteins/physiology ; Peptides/metabolism ; Phosphorylation ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin-Activating Enzymes/genetics ; Ubiquitin-Activating Enzymes/metabolism
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; Saccharomyces cerevisiae Proteins ; polyglutamine (26700-71-0) ; I-kappa B Kinase (EC 2.7.11.10) ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2010-08-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.9.17.12671
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Zs.A 5881: Show issues

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Article ; Online: Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

Wakida, Nicole M / Lau, Alice L / Nguyen, Jessica / Cruz, Gladys Mae S / Fote, Gianna M / Steffan, Joan S / Thompson, Leslie M / Berns, Michael W

Journal of Huntington's disease

2022 Volume 11, Issue 1, Page(s) 25–33

Abstract: Background: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and ...

Abstract	Background: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression. Objective: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. Methods: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. Results: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. Conclusion: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.
MeSH term(s)	Animals ; Astrocytes/pathology ; Corpus Striatum/pathology ; Disease Models, Animal ; Huntington Disease/pathology ; Mice ; Mice, Transgenic ; Phagocytosis
Language	English
Publishing date	2022-03-07
Publishing country	Netherlands
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	2673033-9
ISSN	1879-6400 ; 1879-6397
ISSN (online)	1879-6400
ISSN	1879-6397
DOI	10.3233/JHD-210502
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Article ; Online: Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.

Fote, Gianna M / Geller, Nicolette R / Efstathiou, Nikolaos E / Hendricks, Nathan / Vavvas, Demetrios G / Reidling, Jack C / Thompson, Leslie M / Steffan, Joan S

Journal of cell science

2022 Volume 135, Issue 2

Abstract: The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, ... ...

Abstract	The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	Alzheimer Disease/genetics ; Animals ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Autophagy ; Lysosomes ; Mice ; Protein Isoforms/genetics ; Proteomics
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E ; Protein Isoforms
Language	English
Publishing date	2022-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.258687
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Zs.A 1200: 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)
Zs.MG 14: Show issues

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Article ; Online: Serine residues 13 and 16 are key modulators of mutant huntingtin induced toxicity in Drosophila.

Chatterjee, Megha / Steffan, Joan S / Lukacsovich, Tamas / Marsh, J Lawrence / Agrawal, Namita

Experimental neurology

2020 Volume 338, Page(s) 113463

Abstract: Poly-glutamine expansion near the N-terminus of the huntingtin protein (HTT) is the prime determinant of Huntington's disease (HD) pathology; however, post-translational modifications and protein context are also reported to influence poly-glutamine ... ...

Abstract	Poly-glutamine expansion near the N-terminus of the huntingtin protein (HTT) is the prime determinant of Huntington's disease (HD) pathology; however, post-translational modifications and protein context are also reported to influence poly-glutamine induced HD toxicity. The impact of phosphorylating serine 13/16 of mutant HTT (mHTT) on HD has been documented in cell culture and murine models. However, endogenous processing of the human protein in mammalian systems complicates the interpretations. Therefore, to study the impact of S13/16 phosphorylation on the subcellular behavior of HTT under a controlled genetic background with minimal proteolytic processing of the human protein, we employed Drosophila as the model system. We ectopically expressed full-length (FL) and exon1 fragment of human HTT with phosphomimetic and resistant mutations at serines 13 and 16 in different neuronal populations. Phosphomimetic mHTT aggravates and the phosphoresistant mutation ameliorates mHTT-induced toxicity in the context of both FL- and exon1- mHTT in Drosophila although in all cases FL appears less toxic than exon1. Our observations strongly indicate that the phosphorylation status of S13/16 can affect HD pathology in Drosophila and these residues can be potential targets for affecting HD pathogenesis.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Drosophila ; Humans ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism ; Mutation ; Neurons/pathology ; Phosphorylation ; Protein Processing, Post-Translational ; Serine/genetics ; Serine/metabolism
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Serine (452VLY9402)
Language	English
Publishing date	2020-09-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2020.113463
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Zs.A 184: Show issues

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Article ; Online: Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models.

Schulze-Krebs, Anja / Canneva, Fabio / Stemick, Judith / Plank, Anne-Christine / Harrer, Julia / Bates, Gillian P / Aeschlimann, Daniel / Steffan, Joan S / von Hörsten, Stephan

International journal of molecular sciences

2021 Volume 22, Issue 16

Abstract: Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different ... ...

Abstract	Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different transglutaminases are found in many different tissues, the TG6 isoform is mostly expressed in the CNS. The present study was embarked on/undertaken to investigate expression, distribution and activity of transglutaminases in Huntington disease transgenic rodent models, with a focus on analyzing the involvement of TG6 in the age- and genotype-specific pathological features relating to disease progression in HD transgenic mice and a tgHD transgenic rat model using biochemical, histological and functional assays. Our results demonstrate the physical interaction between TG6 and (mutant) huntingtin by co-immunoprecipitation analysis and the contribution of its enzymatic activity for the total aggregate load in SH-SY5Y cells. In addition, we identify that TG6 expression and activity are especially abundant in the olfactory tubercle and piriform cortex, the regions displaying the highest amount of mHTT aggregates in transgenic rodent models of HD. Furthermore, mHTT aggregates were colocalized within TG6-positive cells. These findings point towards a role of TG6 in disease pathogenesis via mHTT aggregate formation.
MeSH term(s)	Animals ; Disease Models, Animal ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Mice ; Mice, Transgenic ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation ; Neurons/metabolism ; Rats ; Transglutaminases/genetics ; Transglutaminases/metabolism
Chemical Substances	Huntingtin Protein ; Mutant Proteins ; Transglutaminases (EC 2.3.2.13)
Language	English
Publishing date	2021-08-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22168914
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Article ; Online: Author Correction: Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.

Nature communications

2023 Volume 14, Issue 1, Page(s) 1194

Language	English
Publishing date	2023-03-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36930-1
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Article ; Online: Autophagy researchers.

Carra, Serena / Malagoli, Davide / Ney, Paul A / Steffan, Joan S

Autophagy

2013 Volume 10, Issue 2, Page(s) 188–191

MeSH term(s)	Autophagy ; Career Choice ; Humans
Language	English
Publishing date	2013-12-02
Publishing country	United States
Document type	Interview
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.27182
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Zs.A 6741: Show issues

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Article ; Online: Treating the whole body in Huntington's disease.

Carroll, Jeffrey B / Bates, Gillian P / Steffan, Joan / Saft, Carsten / Tabrizi, Sarah J

The Lancet. Neurology

2015 Volume 14, Issue 11, Page(s) 1135–1142

Abstract: Huntington's disease is a genetic neurodegenerative disorder with symptoms that are linked to the progressive dysfunction and neuronal death in corticostriatal circuits. The causative gene (mutated HTT) is widely expressed outside the CNS and several ... ...

Abstract	Huntington's disease is a genetic neurodegenerative disorder with symptoms that are linked to the progressive dysfunction and neuronal death in corticostriatal circuits. The causative gene (mutated HTT) is widely expressed outside the CNS and several peripheral signs of disease, including weight loss and increased proinflammatory signalling, are often seen; however, their importance in the pathophysiology of Huntington's disease is not clear. Studies in animals have shown that features of the disease involving the CNS, including synapse loss and behavioural alterations, are susceptible to modulation by treatments that target tissues and organs outside the CNS. Links between peripheral biology and neurodegeneration have also been shown in other chronic neurodegenerative diseases, suggesting that modulation of these peripheral targets can offer new approaches to therapeutic development. Treatments targeted to tissues and organs outside the CNS might therefore substantially improve the quality of life of patients with Huntington's disease, even in the absence of disease-modifying effects.
MeSH term(s)	Blood ; Central Nervous System/pathology ; Humans ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/pathology ; Huntington Disease/therapy ; Liver/pathology ; Muscles/pathology ; Nerve Tissue Proteins/genetics ; Peripheral Nerves/pathology
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins
Language	English
Publishing date	2015-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2079704-7
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(15)00177-5
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