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2. Endoplasmic reticulum morphology regulation by RTN4 modulates neuronal regeneration by curbing luminal transport

Author

Konno, Tasuku, Parutto, Pierre, Crapart, Cécile C., Davì, Valentina, Bailey, David M.D., Awadelkareem, Mosab Ali, Hockings, Colin, Brown, Aidan I., Xiang, Katherine M., Agrawal, Anamika, Chambers, Joseph E., Vander Werp, Molly J., Koning, Katherine M., Elfari, Louis Mounir, Steen, Sam, Metzakopian, Emmanouil, Westrate, Laura M., Koslover, Elena F., and Avezov, Edward

Published
2024
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3. Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells

Author

Novo, Clara Lopes, Wong, Emily V, Hockings, Colin, Poudel, Chetan, Sheekey, Eleanor, Wiese, Meike, Okkenhaug, Hanneke, Boulton, Simon J, Basu, Srinjan, Walker, Simon, Kaminski Schierle, Gabriele S, Narlikar, Geeta J, and Rugg-Gunn, Peter J

Subjects
Stem Cell Research - Embryonic - Non-Human, Genetics, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Chromosomal Instability, Embryonic Stem Cells, Heterochromatin, Histones, Mice, Mouse Embryonic Stem Cells
Abstract

Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1ɑ droplets in vitro, and modulate heterochromatin into dynamic condensates in ESCs, contributing to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin's biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.

Published
2022

9. VDAC2 enables BAX to mediate apoptosis and limit tumor development

Author

Chin, Hui San, Li, Mark X., Tan, Iris K. L., Ninnis, Robert L., Reljic, Boris, Scicluna, Kristen, Dagley, Laura F., Sandow, Jarrod J., Kelly, Gemma L., Samson, Andre L., Chappaz, Stephane, Khaw, Seong L., Chang, Catherine, Morokoff, Andrew, Brinkmann, Kerstin, Webb, Andrew, Hockings, Colin, Hall, Cathrine M., Kueh, Andrew J., Ryan, Michael T., Kluck, Ruth M., Bouillet, Philippe, Herold, Marco J., Gray, Daniel H. D., Huang, David C. S., van Delft, Mark F., and Dewson, Grant

Published
2018
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11. Endoplasmic Reticulum morphological regulation by RTN4/NOGO modulates neuronal regeneration by slowing luminal transport

Author

Konno, Tasuku, primary, Parutto, Pierre, additional, Bailey, David M. D., additional, Davì, Valentina, additional, Crapart, Cécile, additional, Awadelkareem, Mosab Ali, additional, Hockings, Colin, additional, Brown, Aidan, additional, Xiang, Katherine M., additional, Agrawal, Anamika, additional, Chambers, Joseph E., additional, Werp, Molly Vander, additional, Koning, Katherine, additional, Metzakopian, Emmanouil, additional, Westrate, Laura, additional, Koslover, Elena, additional, and Avezov, Edward, additional

Published
2021
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12. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Author

Lautenschläger, Janin, primary, Wagner-Valladolid, Sara, additional, Stephens, Amberley D., additional, Fernández-Villegas, Ana, additional, Hockings, Colin, additional, Mishra, Ajay, additional, Manton, James D., additional, Fantham, Marcus J., additional, Lu, Meng, additional, Rees, Eric J., additional, Kaminski, Clemens F., additional, and Kaminski Schierle, Gabriele S., additional

Published
2020
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14. Illuminating chromatin compaction in live cells and fixed tissues using SiR-DNA fluorescence lifetime

Author

Hockings, Colin, primary, Poudel, Chetan, additional, Feeney, Kevin A., additional, Novo, Clara L., additional, Hamouda, Mehdi S., additional, Mela, Ioanna, additional, Fernandez-Antoran, David, additional, Vallejo-Ramirez, Pedro P., additional, Rugg-Gunn, Peter J., additional, Chalut, Kevin, additional, Kaminski, Clemens F., additional, and Kaminski-Schierle, Gabriele, additional

Published
2020
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15. A waveguide imaging platform for live‐cell TIRF imaging of neurons over large fields of view

Author

Opstad, Ida S., primary, Ströhl, Florian, additional, Fantham, Marcus, additional, Hockings, Colin, additional, Vanderpoorten, Oliver, additional, Tartwijk, Francesca W., additional, Lin, Julie Qiaojin, additional, Tinguely, Jean‐Claude, additional, Dullo, Firehun T., additional, Kaminski‐Schierle, Gabriele S., additional, Ahluwalia, Balpreet S., additional, and Kaminski, Clemens F., additional

Published
2020
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16. A waveguide imaging platform for live-cell TIRF imaging of neurons over large fields of view

Author

Opstad, Ida S., primary, Ströhl, Florian, additional, Fantham, Marcus, additional, Hockings, Colin, additional, Vanderpoorten, Oliver, additional, van Tartwijk, Francesca W., additional, Lin, Julie Qiaojin, additional, Tinguely, Jean-Claude, additional, Dullo, Firehun T., additional, Kaminski-Schierle, Gabriele S., additional, Ahluwalia, Balpreet S., additional, and Kaminski, Clemens F., additional

Published
2019
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17. Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology

Author

Lautenschläger, Janin, primary, Wagner-Valladolid, Sara, additional, Stephens, Amberley D., additional, Fernández-Villegas, Ana, additional, Hockings, Colin, additional, Mishra, Ajay, additional, Manton, James D., additional, Fantham, Marcus J., additional, Lu, Meng, additional, Rees, Eric J., additional, Kaminski, Clemens F., additional, and Schierle, Gabriele S. Kaminski, additional

Published
2019
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19. Compatibility of RUNX1/ETO fusion protein modules driving CD34+ human progenitor cell expansion

Author

Chen-Wichmann, Linping, primary, Shvartsman, Marina, additional, Preiss, Caro, additional, Hockings, Colin, additional, Windisch, Roland, additional, Redondo Monte, Enric, additional, Leubolt, Georg, additional, Spiekermann, Karsten, additional, Lausen, Jörn, additional, Brendel, Christian, additional, Grez, Manuel, additional, Greif, Philipp A., additional, and Wichmann, Christian, additional

Published
2018
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20. BAX requires VDAC2 to mediate apoptosis and to limit tumor development

Author

Chin, Hui San, primary, van Delft, Mark F., additional, Ninnis, Robert L., additional, Li, Mark X., additional, Tan, Iris K. L., additional, Reljic, Boris, additional, Scicluna, Kristen, additional, Dagley, Laura F., additional, Sandow, Jarrod J., additional, Kelly, Gemma L., additional, Chappaz, Stephane, additional, Khaw, Seong L., additional, Chang, Catherine, additional, Webb, Andrew, additional, Hockings, Colin, additional, Hall, Cathrine M., additional, Kueh, Andrew J., additional, Ryan, Michael T., additional, Kluck, Ruth M., additional, Bouillet, Philippe, additional, Herold, Marco J., additional, Gray, Daniel H. D., additional, Huang, David C. S., additional, and Dewson, Grant, additional

Published
2018
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21. Physiological restraint of Bak by Bcl-xL is essential for cell survival

Author

Lee, Erinna F., primary, Grabow, Stephanie, additional, Chappaz, Stephane, additional, Dewson, Grant, additional, Hockings, Colin, additional, Kluck, Ruth M., additional, Debrincat, Marlyse A., additional, Gray, Daniel H., additional, Witkowski, Matthew T., additional, Evangelista, Marco, additional, Pettikiriarachchi, Anne, additional, Bouillet, Philippe, additional, Lane, Rachael M., additional, Czabotar, Peter E., additional, Colman, Peter M., additional, Smith, Brian J., additional, Kile, Benjamin T., additional, and Fairlie, W. Douglas, additional

Published
2016
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22. BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove.

Author

Tan, Iris K. L., Ma, Stephen B., Kratina, Tobias, Xiang Li, Mark, Dengler, Michael A., Alsop, Amber E., Kluck, Ruth M., Dewson, Grant, and Hockings, Colin

Subjects
APOPTOSIS, PROTEINS, HOMODIMERS, MITOCHONDRIA, HOMOLOGY (Biochemistry)
Abstract

BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (α2-5) and α6 at the rear of BAK, with interaction at α6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein-protein interfaces in BAK self-association are limited to the α2-5 homodimerization domain. [ABSTRACT FROM AUTHOR]

Published
2017
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23. Mcl-1 and Bcl-xLsequestration of Bak confers differential resistance to BH3-only proteins

Author

Hockings, Colin, Alsop, Amber, Fennell, Stephanie, Lee, Erinna, Fairlie, W., Dewson, Grant, and Kluck, Ruth

Abstract

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xLinhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xLand Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xLpreferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xLcould sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-xL. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.

Published
2018
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24. Assembly of the Bak Apoptotic Pore

Author

Ma, Stephen, primary, Hockings, Colin, additional, Anwari, Khatira, additional, Kratina, Tobias, additional, Fennell, Stephanie, additional, Lazarou, Michael, additional, Ryan, Michael T., additional, Kluck, Ruth M., additional, and Dewson, Grant, additional

Published
2013
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25. Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis

Author

Czabotar, Peter E., primary, Westphal, Dana, additional, Dewson, Grant, additional, Ma, Stephen, additional, Hockings, Colin, additional, Fairlie, W. Douglas, additional, Lee, Erinna F., additional, Yao, Shenggen, additional, Robin, Adeline Y., additional, Smith, Brian J., additional, Huang, David C.S., additional, Kluck, Ruth M., additional, Adams, Jerry M., additional, and Colman, Peter M., additional

Published
2013
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26. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Author

Lautenschläger, Janin, Wagner-Valladolid, Sara, Stephens, Amberley D, Fernández-Villegas, Ana, Hockings, Colin, Mishra, Ajay, Manton, James D, Fantham, Marcus J, Lu, Meng, Rees, Eric J, Kaminski, Clemens F, and Kaminski Schierle, Gabriele S

Subjects
amyloid-β (Aβ,), HtrA2/Omi, Nerve Tissue Proteins, protein aggregation, Rats, Sprague-Dawley, neurodegenerative disease, α-synuclein, amyloid-β (AB), Cell Line, Tumor, Animals, Humans, Lon peptidase 1 mitochondrial, protein homeostasis, Amyloid beta-Peptides, Serine-Arginine Splicing Factors, neurodegeneration, HtrA serine peptidase 2, Lon protease, Parkinson Disease, High-Temperature Requirement A Serine Peptidase 2, Peptide Fragments, 3. Good health, Mitochondria, Rats, α-synuclein (a-synuclein), Proteostasis, alpha-Synuclein, Female
Abstract

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

27. A waveguide imaging platform for live-cell TIRF imaging of neurons over large fields of view

Author

Jean-Claude Tinguely, Francesca W. van Tartwijk, Gabriele S. Kaminski-Schierle, Oliver Vanderpoorten, Julie Qiaojin Lin, Clemens F. Kaminski, Florian Ströhl, Balpreet Singh Ahluwalia, Firehun Tsige Dullo, Ida Sundvor Opstad, Marcus Fantham, Colin Hockings, Opstad, Ida S [0000-0003-4462-4600], Ströhl, Florian [0000-0002-2603-0780], Fantham, Marcus [0000-0002-9921-3334], Hockings, Colin [0000-0002-0248-0517], Vanderpoorten, Oliver [0000-0001-5611-470X], van Tartwijk, Francesca W [0000-0002-9795-2571], Lin, Julie Qiaojin [0000-0002-2669-6478], Tinguely, Jean-Claude [0000-0003-4281-0370], Kaminski-Schierle, Gabriele S [0000-0002-1843-2202], Ahluwalia, Balpreet S [0000-0001-7841-6952], Kaminski, Clemens F [0000-0002-5194-0962], and Apollo - University of Cambridge Repository

Subjects
Materials science, Microscope, Cell, General Physics and Astronomy, 02 engineering and technology, 01 natural sciences, Retinal ganglion, General Biochemistry, Genetics and Molecular Biology, law.invention, 010309 optics, 03 medical and health sciences, Optics, law, 0103 physical sciences, Microscopy, medicine, Animals, General Materials Science, 030304 developmental biology, VDP::Mathematics and natural science: 400, Neurons, 0303 health sciences, High contrast, Photons, Total internal reflection fluorescence microscope, business.industry, 010401 analytical chemistry, General Engineering, General Chemistry, VDP::Matematikk og Naturvitenskap: 400, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Rats, medicine.anatomical_structure, Microscopy, Fluorescence, Photonics, 0210 nano-technology, business, Waveguide
Abstract

Large fields of view (FOVs) in total internal reflection fluorescence microscopy (TIRFM) via waveguides have been shown to be highly beneficial for single molecule localisation microscopy on fixed cells [1, 2] and have also been demonstrated for short-term live-imaging of robust cell types [3–5], but not yet for delicate primary neurons nor over extended periods of time. Here, we present a waveguide-based TIRFM set-up for live-cell imaging of demanding samples. Using the developed microscope, referred to as the ChipScope, we demonstrate successful culturing and imaging of fibroblasts, primary rat hippocampal neurons and axons of Xenopus retinal ganglion cells (RGC). The high contrast and gentle illumination mode provided by TIRFM coupled with the exceptionally large excitation areas and superior illumination homogeneity offered by photonic waveguides have potential for a wide application span in neuroscience applications.

Published
2020

28. A Highly Porous Metal-Organic Framework System to Deliver Payloads for Gene Knockdown

Author

Meng Lu, Peyman Z. Moghadam, Michelle H. Teplensky, David Fairen-Jimenez, Omar K. Farha, Chetan Poudel, Marcus Fantham, Clemens F. Kaminski, Sandra Bernaldo de Quirós Fernández, Alina Guna, Colin Hockings, Duncan I. Jodrell, Marta Aragones-Anglada, Frances M. Richards, Gabriele Kaminski Schierle, Peng Li, Poudel, Chetan [0000-0002-8512-9238], Hockings, Colin [0000-0002-0248-0517], Richards, Fran [0000-0001-7947-7853], Jodrell, Duncan [0000-0001-9360-1670], Kaminski Schierle, Gabriele [0000-0002-1843-2202], Kaminski, Clemens [0000-0002-5194-0962], Fairen Jimenez, David [0000-0002-5013-1194], and Apollo - University of Cambridge Repository

Subjects
Small interfering RNA, Endosome, General Chemical Engineering, Endocytic cycle, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Biochemistry, RNA interference, Materials Chemistry, Genetics, Environmental Chemistry, Gene, Gene knockdown, 34 Chemical Sciences, Chemistry, fungi, Biochemistry (medical), RNA, General Chemistry, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Cell biology, FOS: Biological sciences, Drug delivery, 0210 nano-technology, Biotechnology
Abstract

Summary Since first reported, RNA interference (RNAi) has become a widely used tool for cellular genetic knockdown. However, RNA instability and susceptibility to enzymatic degradation have prevented its widespread clinical use. Thus, research efforts are seeking methods to protect the fragile RNA payload during delivery. Here, we report the use of a metal-organic framework (MOF) to load, protect, and deliver small interfering ribonucleic acids (siRNAs). We confirmed the protection of MOF-internalized siRNA from enzymatic degradation. Furthermore, through combined encapsulation of siRNA in the MOF with various cofactors (proton sponge, KALA peptide, and NH4Cl), we show that endosomal retention can be evaded and ensure that gene knockdown is efficacious. In vitro studies after siRNA-MOF complexation demonstrated up to 27% consistent knockdown. We use structured illumination microscopy (SIM) to study the complex’s endocytic uptake. Overall, we demonstrate the potential of these highly porous and biodegradable materials to improve the efficacy and efficiency of future gene therapies.

Published
2019
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