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Article ; Online: Understanding the endo-lysosomal network in neurodegeneration.

Cullen, Peter J / Holstege, Henne / Small, Scott A / St George-Hyslop, Peter

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2024 Volume 379, Issue 1899, Page(s) 20220372

MeSH term(s)	Humans ; Lysosomes ; Alzheimer Disease
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2022.0372
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Article: Does Soluble TREM2 Protect Against Alzheimer's Disease?

Brown, Guy C / St George-Hyslop, Peter

Frontiers in aging neuroscience

2022 Volume 13, Page(s) 834697

Abstract: Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) ... ...

Abstract	Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss
Language	English
Publishing date	2022-01-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.834697
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Article ; Online: Mimicking hypomethylation of FUS requires liquid-liquid phase separation to induce synaptic dysfunctions.

Kim, Seung Chan / Mitchell, Scott J / Qamar, Seema / Whitcomb, Daniel J / Ruepp, Marc-David / St George-Hyslop, Peter / Cho, Kwangwook

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 199

Abstract: The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. ... ...

Abstract	The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS constructs mimicking hypomethylated FUS causes aberrant dendritic FUS condensates in CA1 neurons. These hypomethylated FUS condensates exhibit spontaneous, and activity induced movement within the dendrite. They impair excitatory synaptic transmission, postsynaptic density-95 expression, and dendritic spine plasticity. These neurophysiological defects are dependent upon both the dendritic localisation of the condensates, and their ability to undergo liquid-liquid phase separation. These results indicate that the irreversible liquid-liquid phase separation is a key component of hypomethylated FUS pathophysiology in sporadic FTLD, and this can cause synapse dysfunction in sporadic FTLD.
MeSH term(s)	Humans ; Phase Separation ; RNA-Binding Protein FUS/genetics ; RNA-Binding Protein FUS/metabolism ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration/genetics ; DNA Methylation
Chemical Substances	RNA-Binding Protein FUS ; FUS protein, human
Language	English
Publishing date	2023-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01703-w
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Article ; Online: Spatially non-uniform condensates emerge from dynamically arrested phase separation.

Erkamp, Nadia A / Sneideris, Tomas / Ausserwöger, Hannes / Qian, Daoyuan / Qamar, Seema / Nixon-Abell, Jonathon / St George-Hyslop, Peter / Schmit, Jeremy D / Weitz, David A / Knowles, Tuomas P J

Nature communications

2023 Volume 14, Issue 1, Page(s) 684

Abstract: The formation of biomolecular condensates through phase separation from proteins and nucleic acids is emerging as a spatial organisational principle used broadly by living cells. Many such biomolecular condensates are not, however, homogeneous fluids, ... ...

Abstract	The formation of biomolecular condensates through phase separation from proteins and nucleic acids is emerging as a spatial organisational principle used broadly by living cells. Many such biomolecular condensates are not, however, homogeneous fluids, but possess an internal structure consisting of distinct sub-compartments with different compositions. Notably, condensates can contain compartments that are depleted in the biopolymers that make up the condensate. Here, we show that such double-emulsion condensates emerge via dynamically arrested phase transitions. The combination of a change in composition coupled with a slow response to this change can lead to the nucleation of biopolymer-poor droplets within the polymer-rich condensate phase. Our findings demonstrate that condensates with a complex internal architecture can arise from kinetic, rather than purely thermodynamic driving forces, and provide more generally an avenue to understand and control the internal structure of condensates in vitro and in vivo.
MeSH term(s)	Proteins ; Nucleic Acids ; Biopolymers ; Thermodynamics
Chemical Substances	Proteins ; Nucleic Acids ; Biopolymers
Language	English
Publishing date	2023-02-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36059-1
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Article ; Online: Assembly of the presenilin γ-/ε-secretase complex.

St George-Hyslop, P / Fraser, P E

Journal of neurochemistry

2011 Volume 120 Suppl 1, Page(s) 84–88

Abstract: The presenilin complex is composed of four core proteins (presenilin 1 or presenilin 2, APH1, nicastrin, and PEN2). Several endogenous proteins have been reported to selectively modulate the function of the presenilin complexes; these include ... ...

Abstract	The presenilin complex is composed of four core proteins (presenilin 1 or presenilin 2, APH1, nicastrin, and PEN2). Several endogenous proteins have been reported to selectively modulate the function of the presenilin complexes; these include transmembrane trafficking protein, 21-KD (TMP21), CD147 antigen (basigin), the γ-secretase-activating protein (gSAP), and the orphan G-protein-coupled receptor 3. Because the structure and assembly of these complexes underlies their activity, this review will discuss current work on the assembly of the complex and on presenilin-interacting proteins that regulate secretase activity.
MeSH term(s)	Alzheimer Disease/enzymology ; Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/chemistry ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid Precursor Protein Secretases/physiology ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Animals ; Endopeptidases ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/physiology ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/physiology ; Presenilin-1/chemistry ; Presenilin-1/physiology ; Presenilin-2/chemistry ; Presenilin-2/physiology
Chemical Substances	Amyloid beta-Peptides ; Membrane Proteins ; PSEN1 protein, human ; PSENEN protein, human ; Presenilin-1 ; Presenilin-2 ; APH1A protein, human (EC 3.4.-) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Endopeptidases (EC 3.4.-) ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2011-11-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/j.1471-4159.2011.07505.x
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Article ; Online: The liquid-to-solid transition of FUS is promoted by the condensate surface.

Shen, Yi / Chen, Anqi / Wang, Wenyun / Shen, Yinan / Ruggeri, Francesco Simone / Aime, Stefano / Wang, Zizhao / Qamar, Seema / Espinosa, Jorge R / Garaizar, Adiran / St George-Hyslop, Peter / Collepardo-Guevara, Rosana / Weitz, David A / Vigolo, Daniele / Knowles, Tuomas P J

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

2023 Volume 120, Issue 33, Page(s) e2301366120

Abstract: A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions in biological systems. ... ...

Abstract	A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions in biological systems. Crucially, however, a further liquid-to-solid transition of the condensates can lead to irreversible pathological aggregation and cellular dysfunction associated with the onset and development of neurodegenerative diseases. Despite the importance of this liquid-to-solid transition of proteins, the mechanism by which it is initiated in normally functional condensates is unknown. Here we show, by measuring the changes in structure, dynamics, and mechanics in time and space, that single-component FUS condensates do not uniformly convert to a solid gel, but rather that liquid and gel phases coexist simultaneously within the same condensate, resulting in highly inhomogeneous structures. Furthermore, our results show that this transition originates at the interface between the condensate and the dilute continuous phase, and once initiated, the gelation process propagates toward the center of the condensate. To probe such spatially inhomogeneous rheology during condensate aging, we use a combination of established micropipette aspiration experiments together with two optical techniques, spatial dynamic mapping and reflective confocal dynamic speckle microscopy. These results reveal the importance of the spatiotemporal dimension of the liquid-to-solid transition and highlight the interface of biomolecular condensates as a critical element in driving pathological protein aggregation.
MeSH term(s)	Humans ; Biomolecular Condensates ; Microscopy, Confocal ; Protein Aggregation, Pathological ; Rheology ; RNA-Binding Protein FUS
Chemical Substances	FUS protein, human ; RNA-Binding Protein FUS
Language	English
Publishing date	2023-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2301366120
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Article ; Online: MicroRNA-128 suppresses tau phosphorylation and reduces amyloid-beta accumulation by inhibiting the expression of GSK3β, APPBP2, and mTOR in Alzheimer's disease.

Li, Siwen / Poon, Chi Him / Zhang, Zhigang / Yue, Ming / Chen, Ruijun / Zhang, Yalun / Hossain, Md Farhad / Pan, Yining / Zhao, Jun / Rong, Lei / Chu, Leung Wing / Shea, Yat Fung / Rogaeva, Ekaterina / Tu, Jie / St George-Hyslop, Peter / Lim, Lee Wei / Song, You-Qiang

CNS neuroscience & therapeutics

2023 Volume 29, Issue 7, Page(s) 1848–1864

Abstract: Introduction and aims: Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and ... ...

Abstract	Introduction and aims: Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain-specific miRNA miR-128, encoded by MIR128-1 and MIR128-2, is important for brain development and dysregulated in AD. In this study, the role of miR-128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated. Methods: The effect of miR-128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR-128 overexpression and inhibition. The therapeutic potential of miR-128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR-128-expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR-128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis. Results: Both gain-of-function and loss-of-function studies in AD cellular models reveal that miR-128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR-128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR-128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128-1 transcription, while both C/EBPα and miR-128 expression are inhibited by Aβ. Conclusion: Our findings suggest that miR-128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR-128 in AD, in which Aβ reduces miR-128 expression by inhibiting C/EBPα.
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/metabolism ; MicroRNAs/metabolism ; Phosphorylation ; Glycogen Synthase Kinase 3 beta ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	MicroRNAs ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Amyloid beta-Peptides ; tau Proteins ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Mirn128 microRNA, mouse
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2423461-8
ISSN	1755-5949 ; 1755-5930
ISSN (online)	1755-5949
ISSN	1755-5930
DOI	10.1111/cns.14143
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Article ; Online: Withdrawal: Cytosolic proteins regulate α-synuclein dissociation from presynaptic membranes.

Wislet-Gendebien, Sabine / D'Souza, Cheryl / Kawarai, Toshitaka / St George-Hyslop, Peter / Westaway, David / Fraser, Paul / Tandon, Anurag

The Journal of biological chemistry

2020 Volume 295, Issue 39, Page(s) 13694

Language	English
Publishing date	2020-12-24
Publishing country	United States
Document type	Journal Article ; Retraction of Publication
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.W120.015777
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Article: Alzheimer's disease.

St George-Hyslop, P

Neurobiology of disease

2000 Volume 7, Issue 5, Page(s) 546–548

MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Apolipoproteins E/genetics ; Humans ; Membrane Proteins/genetics ; Presenilin-1 ; Presenilin-2
Chemical Substances	Amyloid beta-Protein Precursor ; Apolipoproteins E ; Membrane Proteins ; PSEN1 protein, human ; PSEN2 protein, human ; Presenilin-1 ; Presenilin-2
Language	English
Publishing date	2000-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1006/nbdi.2000.0352
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Article ; Online: The liquid-to-solid transition of FUS is promoted by the condensate surface

Shen, Yi / Chen, Anqi / Wang, Wenyun / Shen, Yinan / Ruggeri, Francesco Simone / Aime, Stefano / Wang, Zizhao / Qamar, Seema / Garaizar, Adiran / Espinosa, Jorge R. / St George-Hyslop, Peter / Collepardo-Guevara, Rosana / Weitz, David A. / Vigolo, Daniele / Knowles, Tuomas P.J.

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

2023 Volume 120, Issue 33

Abstract	A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions in biological systems. Crucially, however, a further liquid-to-solid transition of the condensates can lead to irreversible pathological aggregation and cellular dysfunction associated with the onset and development of neurodegenerative diseases. Despite the importance of this liquid-to-solid transition of proteins, the mechanism by which it is initiated in normally functional condensates is unknown. Here we show, by measuring the changes in structure, dynamics, and mechanics in time and space, that single-component FUS condensates do not uniformly convert to a solid gel, but rather that liquid and gel phases coexist simultaneously within the same condensate, resulting in highly inhomogeneous structures. Furthermore, our results show that this transition originates at the interface between the condensate and the dilute continuous phase, and once initiated, the gelation process propagates toward the center of the condensate. To probe such spatially inhomogeneous rheology during condensate aging, we use a combination of established micropipette aspiration experiments together with two optical techniques, spatial dynamic mapping and reflective confocal dynamic speckle microscopy. These results reveal the importance of the spatiotemporal dimension of the liquid-to-solid transition and highlight the interface of biomolecular condensates as a critical element in driving pathological protein aggregation.
Keywords	biomolecular condensates ; optics ; protein
Subject code	612
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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