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Article ; Online: Microbial specialization by prions.

Newby, Gregory A / Kayatekin, Can

2018 , Page(s) 1–5

Abstract: Microbial prions facilitate a variety of phenotypic switches. Recently-developed tools that can directly interrogate, in the living cell, the aggregation state of a protein have enabled a wider range of experiments for prion-mediated behaviors. With such ...

Abstract	Microbial prions facilitate a variety of phenotypic switches. Recently-developed tools that can directly interrogate, in the living cell, the aggregation state of a protein have enabled a wider range of experiments for prion-mediated behaviors. With such tools, the roles of the yeast prion [SWI
Language	English
Publishing date	2018-07-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267671-5
ISSN	1933-690X ; 1933-690X
ISSN (online)	1933-690X
ISSN	1933-690X
DOI	10.1080/19336896.2018.1469945
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Article: Murine Models of Lysosomal Storage Diseases Exhibit Differences in Brain Protein Aggregation and Neuroinflammation.

Clarke, Jennifer / Kayatekin, Can / Viel, Catherine / Shihabuddin, Lamya / Sardi, Sergio Pablo

Biomedicines

2021 Volume 9, Issue 5

Abstract: Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson's disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of ... ...

Abstract	Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson's disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann-Pick A (NPA), Hurler, Pompe and Niemann-Pick C (NPC) diseases and assessed for the presence of Lewy body-like pathology (proteinase K-resistant α-synuclein and tau aggregates) and neuroinflammation (microglial Iba1 and astrocytic GFAP) by immunofluorescence. All seven LSD models exhibited evidence of proteinopathy and/or inflammation in the central nervous system (CNS). However, these phenotypes were divergent. Gaucher and Fabry mouse models displayed proteinase K-resistant α-synuclein and tau aggregates but no neuroinflammation; whereas Sandhoff, NPA and NPC showed marked neuroinflammation and no overt proteinopathy. Pompe disease animals uniquely displayed widespread distribution of tau aggregates accompanied by moderate microglial activation. Hurler mice also demonstrated proteinopathy and microglial activation. The present study demonstrated additional links between LSDs and pathogenic phenotypes that are hallmarks of synucleinopathies. The data suggest that lysosomal dysregulation can contribute to brain region-specific protein aggregation and induce widespread neuroinflammation in the brain. However, only a few LSD models examined exhibited phenotypes consistent with synucleinopathies. While no model can recapitulate the complexity of PD, they can enable the study of specific pathways and mechanisms contributing to disease pathophysiology. The present study provides evidence that there are existing, previously unutilized mouse models that can be employed to study pathogenic mechanisms and gain insights into potential PD subtypes, helping to determine if they are amenable to pathway-specific therapeutic interventions.
Language	English
Publishing date	2021-04-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9050446
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Article ; Online: Friction-Limited Folding of Disulfide-Reduced Monomeric SOD1.

Cohen, Noah R / Kayatekin, Can / Zitzewitz, Jill A / Bilsel, Osman / Matthews, C R

Biophysical journal

2020 Volume 118, Issue 8, Page(s) 1992–2000

Abstract: The folding reaction of a stable monomeric variant of Cu/Zn superoxide dismutase (mSOD1), an enzyme responsible for the conversion of superoxide free radicals into hydrogen peroxide and oxygen, is known to be among the slowest folding processes that ... ...

Abstract	The folding reaction of a stable monomeric variant of Cu/Zn superoxide dismutase (mSOD1), an enzyme responsible for the conversion of superoxide free radicals into hydrogen peroxide and oxygen, is known to be among the slowest folding processes that adhere to two-state behavior. The long lifetime, ∼10 s, of the unfolded state presents ample opportunities for the polypeptide chain to transiently sample nonnative structures before the formation of the productive folding transition state. We recently observed the formation of a nonnative structure in a peptide model of the C-terminus of SOD1, a sequence that might serve as a potential source of internal chain friction-limited folding. To test for friction-limited folding, we performed a comprehensive thermodynamic and kinetic analysis of the folding mechanism of mSOD1 in the presence of the viscogens glycerol and glucose. Using a, to our knowledge, novel analysis of the folding reactions, we found the disulfide-reduced form of the protein that exposes the C-terminal sequence, but not its disulfide-oxidized counterpart that protects it, experiences internal chain friction during folding. The sensitivity of the internal friction to the disulfide bond status suggests that one or both of the cross-linked regions play a critical role in driving the friction-limited folding. We speculate that the molecular mechanisms giving rise to the internal friction of disulfide-reduced mSOD1 might play a role in the amyotrophic lateral sclerosis-linked aggregation of SOD1.
MeSH term(s)	Amyotrophic Lateral Sclerosis ; Disulfides ; Friction ; Humans ; Kinetics ; Mutation ; Protein Folding ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism
Chemical Substances	Disulfides ; SOD1 protein, human ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2020-03-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2020.02.028
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Article ; Online: Persistent Activation of mRNA Translation by Transient Hsp90 Inhibition.

Tsvetkov, Peter / Eisen, Timothy J / Heinrich, Sven U / Brune, Zarina / Hallacli, Erinc / Newby, Greg A / Kayatekin, Can / Pincus, David / Lindquist, Susan

Cell reports

2020 Volume 32, Issue 10, Page(s) 108149

Language	English
Publishing date	2020-09-09
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108149
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Article ; Online: Persistent Activation of mRNA Translation by Transient Hsp90 Inhibition.

Tsvetkov, Peter / Eisen, Timothy J / Heinrich, Sven U / Brune, Zarina / Hallacli, Erinc / Newby, Greg A / Kayatekin, Can / Pincus, David / Lindquist, Susan

Cell reports

2020 Volume 32, Issue 6, Page(s) 108001

Abstract: The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a role promoting the evolution of new heritable traits. To better understand how Hsp90 can affect mRNA translation, we screen more than 1,600 factors involved in ... ...

Abstract	The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a role promoting the evolution of new heritable traits. To better understand how Hsp90 can affect mRNA translation, we screen more than 1,600 factors involved in mRNA regulation for physical interactions with Hsp90 in human cells. The mRNA binding protein CPEB2 strongly binds Hsp90 via its prion domain. In a yeast model, transient inhibition of Hsp90 results in persistent activation of a CPEB translation reporter even in the absence of exogenous CPEB that persists for 30 generations after the inhibitor is removed. Ribosomal profiling reveals that some endogenous yeast mRNAs, including HAC1, show a persistent change in translation efficiency following transient Hsp90 inhibition. Thus, transient loss of Hsp90 function can promote a nongenetic inheritance of a translational state affecting specific mRNAs, introducing a mechanism by which Hsp90 can promote phenotypic variation.
MeSH term(s)	HSP90 Heat-Shock Proteins/metabolism ; Humans ; Protein Biosynthesis ; RNA, Messenger/metabolism
Chemical Substances	HSP90 Heat-Shock Proteins ; RNA, Messenger
Language	English
Publishing date	2020-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108001
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Article ; Online: Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.

Viel, Catherine / Clarke, Jennifer / Kayatekin, Can / Richards, Amy M / Chiang, Ming Sum R / Park, Hyejung / Wang, Bing / Shihabuddin, Lamya S / Sardi, S Pablo

Scientific reports

2021 Volume 11, Issue 1, Page(s) 20945

Abstract: Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele ... ...

Abstract	Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.
MeSH term(s)	Animals ; Carbamates/pharmacology ; Disease Models, Animal ; Glucosylceramidase/metabolism ; Glucosylceramides/metabolism ; Glucosyltransferases/antagonists & inhibitors ; Hippocampus/drug effects ; Hippocampus/metabolism ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Parkinson Disease/metabolism ; Quinuclidines/pharmacology ; Synucleinopathies/drug therapy ; Synucleinopathies/metabolism
Chemical Substances	Carbamates ; Glucosylceramides ; Quinuclidines ; venglustat (BLP1XA3FZA) ; Glucosyltransferases (EC 2.4.1.-) ; ceramide glucosyltransferase (EC 2.4.1.80) ; Gba protein, mouse (EC 3.2.1.45) ; Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2021-10-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-00404-5
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Article ; Online: Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy.

Wang, Hongge / Davison, Matthew D / Kramer, Martin L / Qiu, Weiliang / Gladysheva, Tatiana / Chiang, Ruby M S / Kayatekin, Can / Nascene, David R / Taghizadeh, Leyla A / King, Carina J / Nolan, Erin E / Gupta, Ashish O / Orchard, Paul J / Lund, Troy C

Cells

2022 Volume 11, Issue 5

Abstract: Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation ... ...

Abstract	Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in
MeSH term(s)	Adrenoleukodystrophy/diagnosis ; Adrenoleukodystrophy/genetics ; Adrenoleukodystrophy/metabolism ; Biomarkers/metabolism ; Child ; Humans ; Intermediate Filaments/metabolism ; Male ; Sweden
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11050913
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Article: Enthalpic Barriers Dominate the Folding and Unfolding of the Human Cu, Zn Superoxide Dismutase Monomer

Kayatekin, Can / Cohen, Noah R / Matthews, C. Robert

Journal of molecular biology. 2012 Dec. 7, v. 424, no. 3-4

2012

Abstract: The rate-limiting step in the formation of the native dimeric state of human Cu, Zn superoxide dismutase (SOD1) is a very slow monomer folding reaction that governs the lifetime of its unfolded state. Mutations at dozens of sites in SOD1 are known to ... ...

Abstract	The rate-limiting step in the formation of the native dimeric state of human Cu, Zn superoxide dismutase (SOD1) is a very slow monomer folding reaction that governs the lifetime of its unfolded state. Mutations at dozens of sites in SOD1 are known to cause a fatal motor neuron disease, amyotrophic lateral sclerosis, and recent experiments implicate the unfolded state as a source of soluble oligomers and histologically observable aggregates thought to be responsible for toxicity. To determine the thermodynamic properties of the transition state ensemble (TSE) limiting the folding of this high‐contact‐order β-sandwich motif, we performed a combined thermal/urea denaturation thermodynamic/kinetic analysis. The barriers to folding and unfolding are dominated by the activation enthalpy at 298K and neutral pH; the activation entropy is favorable and reduces the barrier height for both reactions. The absence of secondary structure formation or large-scale chain collapse prior to crossing the barrier for folding led to the conclusion that dehydration of nonpolar surfaces in the TSE is responsible for the large and positive activation enthalpy. Although the activation entropy favors the folding reaction, the transition from the unfolded state to the native state is entropically disfavored at 298K. The opposing entropic contributions to the free energies of the TSE and the native state during folding provide insights into structural properties of the TSE. The results also imply a crucial role for water in governing the productive folding reaction and enhancing the propensity for the aggregation of SOD1.
Keywords	denaturation ; enthalpy ; entropy ; humans ; mutation ; pH ; sclerosis ; superoxide dismutase ; toxicity ; urea
Language	English
Dates of publication	2012-1207
Size	p. 192-202.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2012.09.009
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Enthalpic barriers dominate the folding and unfolding of the human Cu, Zn superoxide dismutase monomer.

Kayatekin, Can / Cohen, Noah R / Matthews, C Robert

Journal of molecular biology

2012 Volume 424, Issue 3-4, Page(s) 192–202

Abstract	The rate-limiting step in the formation of the native dimeric state of human Cu, Zn superoxide dismutase (SOD1) is a very slow monomer folding reaction that governs the lifetime of its unfolded state. Mutations at dozens of sites in SOD1 are known to cause a fatal motor neuron disease, amyotrophic lateral sclerosis, and recent experiments implicate the unfolded state as a source of soluble oligomers and histologically observable aggregates thought to be responsible for toxicity. To determine the thermodynamic properties of the transition state ensemble (TSE) limiting the folding of this high-contact-order β-sandwich motif, we performed a combined thermal/urea denaturation thermodynamic/kinetic analysis. The barriers to folding and unfolding are dominated by the activation enthalpy at 298 K and neutral pH; the activation entropy is favorable and reduces the barrier height for both reactions. The absence of secondary structure formation or large-scale chain collapse prior to crossing the barrier for folding led to the conclusion that dehydration of nonpolar surfaces in the TSE is responsible for the large and positive activation enthalpy. Although the activation entropy favors the folding reaction, the transition from the unfolded state to the native state is entropically disfavored at 298 K. The opposing entropic contributions to the free energies of the TSE and the native state during folding provide insights into structural properties of the TSE. The results also imply a crucial role for water in governing the productive folding reaction and enhancing the propensity for the aggregation of SOD1.
MeSH term(s)	Humans ; Hydrogen-Ion Concentration ; Models, Molecular ; Protein Conformation ; Protein Denaturation ; Protein Folding ; Superoxide Dismutase/chemistry ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Temperature ; Thermodynamics ; Urea/metabolism
Chemical Substances	SOD1 protein, human ; Urea (8W8T17847W) ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2012-09-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2012.09.009
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Article ; Online: Luminidependens (LD) is an Arabidopsis protein with prion behavior.

Chakrabortee, Sohini / Kayatekin, Can / Newby, Greg A / Mendillo, Marc L / Lancaster, Alex / Lindquist, Susan

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 113, Issue 21, Page(s) 6065–6070

Abstract: Prion proteins provide a unique mode of biochemical memory through self-perpetuating changes in protein conformation and function. They have been studied in fungi and mammals, but not yet identified in plants. Using a computational model, we identified ... ...

Abstract	Prion proteins provide a unique mode of biochemical memory through self-perpetuating changes in protein conformation and function. They have been studied in fungi and mammals, but not yet identified in plants. Using a computational model, we identified candidate prion domains (PrDs) in nearly 500 plant proteins. Plant flowering is of particular interest with respect to biological memory, because its regulation involves remembering and integrating previously experienced environmental conditions. We investigated the prion-forming capacity of three prion candidates involved in flowering using a yeast model, where prion attributes are well defined and readily tested. In yeast, prions heritably change protein functions by templating monomers into higher-order assemblies. For most yeast prions, the capacity to convert into a prion resides in a distinct prion domain. Thus, new prion-forming domains can be identified by functional complementation of a known prion domain. The prion-like domains (PrDs) of all three of the tested proteins formed higher-order oligomers. Uniquely, the Luminidependens PrD (LDPrD) fully replaced the prion-domain functions of a well-characterized yeast prion, Sup35. Our results suggest that prion-like conformational switches are evolutionarily conserved and might function in a wide variety of normal biological processes.
MeSH term(s)	Arabidopsis/chemistry ; Arabidopsis Proteins/chemistry ; Models, Molecular ; Peptide Termination Factors/chemistry ; Prion Proteins/chemistry ; Protein Domains ; Saccharomyces cerevisiae Proteins/chemistry
Chemical Substances	Arabidopsis Proteins ; LD protein, Arabidopsis ; Peptide Termination Factors ; Prion Proteins ; SUP35 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2016-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1604478113
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