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Article: SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism.

Aryal, Shivani / Chen, Shawei / Burbach, Kyle F / Yang, Yan / Capano, Lucia S / Kim, Woo Kyung / Bragg, D Cristopher / Yoo, Andrew

Research square

2024

Abstract: Background X-linked Dystonia-Parkinsonism(XDP) is an adult-onset neurodegenerative disorder that results in the loss of striatal medium spiny neurons (MSNs). XDP is associated with disease-specific mutations in and around ... ...

Abstract	Background X-linked Dystonia-Parkinsonism(XDP) is an adult-onset neurodegenerative disorder that results in the loss of striatal medium spiny neurons (MSNs). XDP is associated with disease-specific mutations in and around the
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-4068432/v1
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Article: Longitudinal modeling of human neuronal aging identifies RCAN1-TFEB pathway contributing to neurodegeneration of Huntington's disease.

Lee, Seong Won / Oh, Young Mi / Victor, Matheus B / Strunilin, Ilya / Chen, Shawei / Dahiya, Sonika / Dolle, Roland E / Pak, Stephen C / Silverman, Gary A / Perlmutter, David H / Yoo, Andrew S

Research square

2023

Abstract: Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, we perform ... ...

Abstract	Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs), a primary neuronal subtype affected in Huntington's disease (HD), identified pathways associated with RCAN1, a negative regulator of calcineurin. Notably, RCAN1 undergoes age-dependent increase at the protein level detected in reprogrammed MSNs as well as in human postmortem striatum. In patient-derived MSNs of adult-onset HD (HD-MSNs), counteracting
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2815300/v1
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Article ; Online: Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration.

Lee, Seong Won / Oh, Young Mi / Victor, Matheus B / Yang, Yan / Chen, Shawei / Strunilin, Ilya / Dahiya, Sonika / Dolle, Roland E / Pak, Stephen C / Silverman, Gary A / Perlmutter, David H / Yoo, Andrew S

Nature aging

2023 Volume 4, Issue 1, Page(s) 95–109

Abstract: Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal ... ...

Abstract	Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington's disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington's disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB's nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1-calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington's disease.
MeSH term(s)	Humans ; Aged ; Calcineurin/genetics ; Huntington Disease/genetics ; Aging/genetics ; Transcription Factors/metabolism ; Corpus Striatum/metabolism ; DNA-Binding Proteins/metabolism ; Muscle Proteins/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
Chemical Substances	Calcineurin (EC 3.1.3.16) ; Transcription Factors ; RCAN1 protein, human ; DNA-Binding Proteins ; Muscle Proteins ; TFEB protein, human ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ISSN	2662-8465
ISSN (online)	2662-8465
DOI	10.1038/s43587-023-00538-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy.

Oh, Young Mi / Lee, Seong Won / Kim, Woo Kyung / Chen, Shawei / Church, Victoria A / Cates, Kitra / Li, Tiandao / Zhang, Bo / Dolle, Roland E / Dahiya, Sonika / Pak, Stephen C / Silverman, Gary A / Perlmutter, David H / Yoo, Andrew S

Nature neuroscience

2022 Volume 25, Issue 11, Page(s) 1420–1433

Abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium ...

Abstract	Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3' untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.
MeSH term(s)	Humans ; Animals ; Huntington Disease/pathology ; Corpus Striatum/physiology ; Neurons/physiology ; Autophagy ; MicroRNAs/genetics ; Disease Progression ; Disease Models, Animal
Chemical Substances	MicroRNAs
Language	English
Publishing date	2022-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-022-01185-4
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Zs.A 4891: 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)
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Article: Endogenous recapitulation of Alzheimer's disease neuropathology through human 3D direct neuronal reprogramming.

bioRxiv : the preprint server for biology

2023

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal ... ...

Abstract	Alzheimer's disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular Aβ deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with β- or γ-secretase inhibitors in LOAD patient-derived neurons and spheroids before Aβ deposit formation significantly lowered Aβ deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed Aβ deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between Aβ accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.
Language	English
Publishing date	2023-05-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.24.542155
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Article: Allosteric Activation and Contrasting Properties of l-Serine Dehydratase Types 1 and 2

Chen, Shawei / Xu Xiao Lan / Grant Gregory A

Biochemistry. 2012 July 03, v. 51, no. 26

2012

Abstract: Bacterial l-serine dehydratases differ from mammalian l- and d-serine dehydratases and bacterial d-serine dehydratases by the presence of an ironâsulfur center rather than a pyridoxyl phosphate prosthetic group. They exist in two forms, types 1 and 2, ... ...

Abstract	Bacterial l-serine dehydratases differ from mammalian l- and d-serine dehydratases and bacterial d-serine dehydratases by the presence of an ironâsulfur center rather than a pyridoxyl phosphate prosthetic group. They exist in two forms, types 1 and 2, distinguished by their sequence and oligomeric configuration. Both types contain an ASB domain, and the type 1 enzymes also contain an ACT domain in a tandem arrangement with the ASB domain like that in type 1 d-3-phosphoglycerate dehydrogenases (PGDHs). This investigation reveals striking kinetic differences between l-serine dehydratases from Bacillus subtilis (bsLSD, type 1) and Legionella pneumophila (lpLSD, type 2). lpLSD is activated by monovalent cations and inhibited by monovalent anions. bsLSD is strongly activated by cations, particularly potassium, and shows a mixed response to anions. Flouride is a competitive inhibitor for lpLSD but an apparent activator for bsLSD at low concentrations and an inhibitor at high concentrations. The reaction products, pyruvate and ammonia, also act as activators but to different extents for each type. Pyruvate activation is competitive with l-serine, but activation of the enzyme is not compatible with it simply competing for binding at the active site and suggests the presence of a second, allosteric site. Because activation can be eliminated by higher levels of l-serine, it may be that this second site is actually a second serine binding site. This is consistent with type 1 PGDH in which the ASB domain functions as a second site for substrate binding and activation.
Keywords	Bacillus subtilis ; Legionella pneumophila ; active sites ; ammonia ; anions ; binding sites ; cations ; enzyme activation ; enzymes ; mammals ; phosphates ; potassium ; pyruvic acid ; serine
Language	English
Dates of publication	2012-0703
Size	p. 5320-5328.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Fbi300523p
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 217: Show issues

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Article ; Online: Allosteric activation and contrasting properties of L-serine dehydratase types 1 and 2.

Chen, Shawei / Xu, Xiao Lan / Grant, Gregory A

Biochemistry

2012 Volume 51, Issue 26, Page(s) 5320–5328

Abstract: Bacterial L-serine dehydratases differ from mammalian L- and D-serine dehydratases and bacterial D-serine dehydratases by the presence of an iron-sulfur center rather than a pyridoxyl phosphate prosthetic group. They exist in two forms, types 1 and 2, ... ...

Abstract	Bacterial L-serine dehydratases differ from mammalian L- and D-serine dehydratases and bacterial D-serine dehydratases by the presence of an iron-sulfur center rather than a pyridoxyl phosphate prosthetic group. They exist in two forms, types 1 and 2, distinguished by their sequence and oligomeric configuration. Both types contain an ASB domain, and the type 1 enzymes also contain an ACT domain in a tandem arrangement with the ASB domain like that in type 1 D-3-phosphoglycerate dehydrogenases (PGDHs). This investigation reveals striking kinetic differences between L-serine dehydratases from Bacillus subtilis (bsLSD, type 1) and Legionella pneumophila (lpLSD, type 2). lpLSD is activated by monovalent cations and inhibited by monovalent anions. bsLSD is strongly activated by cations, particularly potassium, and shows a mixed response to anions. Flouride is a competitive inhibitor for lpLSD but an apparent activator for bsLSD at low concentrations and an inhibitor at high concentrations. The reaction products, pyruvate and ammonia, also act as activators but to different extents for each type. Pyruvate activation is competitive with L-serine, but activation of the enzyme is not compatible with it simply competing for binding at the active site and suggests the presence of a second, allosteric site. Because activation can be eliminated by higher levels of L-serine, it may be that this second site is actually a second serine binding site. This is consistent with type 1 PGDH in which the ASB domain functions as a second site for substrate binding and activation.
MeSH term(s)	Allosteric Regulation ; Bacillus subtilis/enzymology ; L-Serine Dehydratase/metabolism ; Legionella pneumophila/enzymology ; Models, Biological
Chemical Substances	L-Serine Dehydratase (EC 4.3.1.17)
Language	English
Publishing date	2012-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi300523p
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Zs.A 217: Show issues

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Article ; Online: Kinetic, mutagenic, and structural homology analysis of L-serine dehydratase from Legionella pneumophila.

Xu, Xiao Lan / Chen, Shawei / Grant, Gregory A

Archives of biochemistry and biophysics

2011 Volume 515, Issue 1-2, Page(s) 28–36

Abstract: A structural database search has revealed that the same fold found in the allosteric substrate binding (ASB) domain of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase (PGDH) is found in l-serine dehydratase from Legionella pneumophila. The ... ...

Abstract	A structural database search has revealed that the same fold found in the allosteric substrate binding (ASB) domain of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase (PGDH) is found in l-serine dehydratase from Legionella pneumophila. The M. tuberculosis PGDH ASB domain functions in the control of catalytic activity. Bacterial l-serine dehydratases are 4Fe-4S proteins that convert l-serine to pyruvate and ammonia. Sequence homology reveals two types depending on whether their α and β domains are on the same (Type 2) or separate (Type 1) polypeptides. The α domains contain the catalytic iron-sulfur center while the β domains do not yet have a described function, but the structural homology with PGDH suggests a regulatory role. Type 1 β domains also contain additional sequence homologous to PGDH ACT domains. A continuous assay for l-serine dehydratase is used to demonstrate homotropic cooperativity, a broad pH range, and essential irreversibility. Product inhibition analysis reveals a Uni-Bi ordered mechanism with ammonia dissociating before pyruvate. l-Threonine is a poor substrate and l-cysteine and d-serine are competitive inhibitors with K(i) values that differ by almost 10-fold from those reported for Escherichia colil-serine dehydratase. Mutagenesis identifies the three cysteine residues at the active site that anchor the iron-sulfur complex.
MeSH term(s)	Amino Acid Sequence ; Base Sequence ; Catalytic Domain ; DNA Primers ; Hydrogen-Ion Concentration ; Kinetics ; L-Serine Dehydratase/antagonists & inhibitors ; L-Serine Dehydratase/chemistry ; L-Serine Dehydratase/metabolism ; Legionella pneumophila/enzymology ; Models, Molecular ; Molecular Sequence Data ; Mutagens ; Protein Conformation ; Sequence Homology, Amino Acid
Chemical Substances	DNA Primers ; Mutagens ; L-Serine Dehydratase (EC 4.3.1.17)
Language	English
Publishing date	2011-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2011.08.005
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Article ; Online: Comparison of Type 1 D-3-phosphoglycerate dehydrogenases reveals unique regulation in pathogenic Mycobacteria.

Xu, Xiao Lan / Chen, Shawei / Salinas, Nichole D / Tolia, Niraj H / Grant, Gregory A

Archives of biochemistry and biophysics

2015 Volume 570, Page(s) 32–39

Abstract: D-3-phosphoglycerate dehydrogenases (PGDH) from all organisms catalyze the conversion of D-3-phosphoglycerate to phosphohydroxypyruvate as the first step in the biosynthesis of l-serine. This investigation compares the properties of Type 1 PGDHs from ... ...

Abstract	D-3-phosphoglycerate dehydrogenases (PGDH) from all organisms catalyze the conversion of D-3-phosphoglycerate to phosphohydroxypyruvate as the first step in the biosynthesis of l-serine. This investigation compares the properties of Type 1 PGDHs from seven different species and demonstrates that conserved residues in the ACT and ASB domains of some allow l-serine to act as a feedback inhibitor at low micromolar concentrations. In addition, the serine sensitivity is dependent on the presence of phosphate ions. These residues are most highly conserved among PGDHs from the actinomycetales family, but only certain pathogenic mycobacteria appear to have the full complement of residues required for high sensitivity to serine. These basic residues are also responsible for the presence of dual pH optima in the acidic region that is also phosphate dependent. Analytical ultracentrifugation analysis demonstrates that the dual pH optima do not require changes in oligomeric state. This study also demonstrates that substrate inhibition is a common feature of Type 1 PGDHs and that it is suppressed by phosphate, indicating that phosphate likely interacts at both the catalytic and regulatory sites. The unique features resulting from the complement of basic residues conserved in pathogenic mycobacteria may impart important metabolic advantages to these organisms.
MeSH term(s)	Amino Acid Sequence ; Bacillus subtilis/metabolism ; Catalysis ; Corynebacterium glutamicum/metabolism ; DNA Mutational Analysis ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Bacterial ; Gene Expression Regulation, Enzymologic ; Hydrogen-Ion Concentration ; Ions ; Models, Molecular ; Molecular Sequence Data ; Mycobacterium/enzymology ; Mycobacterium marinum/metabolism ; Mycobacterium smegmatis/metabolism ; Mycobacterium tuberculosis/metabolism ; Phosphates/chemistry ; Phosphoglycerate Dehydrogenase/metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Serine/chemistry ; Streptomyces coelicolor/metabolism ; Substrate Specificity
Chemical Substances	Ions ; Phosphates ; Serine (452VLY9402) ; Phosphoglycerate Dehydrogenase (EC 1.1.1.95)
Language	English
Publishing date	2015-03-15
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2015.02.008
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Article ; Online: Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy.

Fox, Leora M / Kim, Kiryung / Johnson, Christopher W / Chen, Shawei / Croce, Katherine R / Victor, Matheus B / Eenjes, Evelien / Bosco, Joan R / Randolph, Lisa K / Dragatsis, Ioannis / Dragich, Joanna M / Yoo, Andrew S / Yamamoto, Ai

Neuron

2019 Volume 105, Issue 5, Page(s) 813–821.e6

Abstract: Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor ...

Abstract	Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Age of Onset ; Animals ; Autophagy-Related Proteins/genetics ; Cell Death/genetics ; Disease Models, Animal ; Female ; Fibroblasts ; Humans ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Huntington Disease/physiopathology ; Macroautophagy/genetics ; Male ; Mice ; Mice, Knockout ; Neurons/metabolism ; Protein Aggregation, Pathological/genetics ; Protein Aggregation, Pathological/metabolism ; Protein Aggregation, Pathological/physiopathology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; Huntingtin Protein ; WDFY3 protein, human ; Wdfy3 protein, mouse
Language	English
Publishing date	2019-12-30
Publishing country	United States
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	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2019.12.003
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Zs.A 2496: 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)
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