OptoGranules reveal the evolution of stress granules to ALS-FTD pathology
Posted on: 7 July 2018
Preprint posted on 18 June 2018
Optogenetic tool to identify and study how chronic stress causes the formation of pathogenic inclusions in neurodegenerative diseases.
Selected by Srivats Venkataramanan
Categories: biochemistry, cell biology, molecular biology, neuroscience, pathology
Context:
Amyotrophic Lateral Sclerosis (ALS – also known as Lou Gehrig’s Disease), is a progressive, fatal neurodegenerative disease. Both ALS and a clinically overlapping condition, Fronto-Temporal Dementia (FTD) are characterized by insoluble cytoplasmic aggregates within affected neurons. The appearance of these inclusions precedes neuronal destruction, and they are typically highly enriched in a hyper-phosphorylated and ubiquitinated form of a 43KDa DNA-binding protein, TDP-43. In addition, these pathological inclusions also host a variety of RNA-binding proteins, as well as mRNA [1].
All of the proteins within these inclusions are also components of stress granules (SGs), cytoplasmic mRNP granules that form when cells experience a wide variety of stresses that also repress mRNA translation. In fact, translation repression has long been considered a pre-requisite for endogenous SG formation. The similarities between the composition of these transient, dynamic SGs, and the persistent, pathological cytoplasmic inclusions seen in ALS affected neurons have led many to hypothesize that the formation of these inclusions might relate to altered/perturbed stress granule dynamics [2]. As support for this hypothesis, mutations in a number of SG-related proteins are strongly correlated with the occurrence of ALS [3].
However, the hypothesis that SGs are required for the formation of pathological inclusions has never been robustly tested, and neither have any potential mechanistic connections between the two addressed. The challenges have largely been technical. Since most SG-associated proteins are RNA-binding proteins and all of them have other cellular functions, abrogating SG formation via genetic methods causes too many pleiotropic effects to provide a clean assay [4]. On the other hand, methods to artificially induce SGs rely on subjecting cells to external stressors, all of which introduce the confounding variable of translation repression (most often via the inhibitory phosphorylation of initiation faction eIF2⍺) [5]. In this preprint, Zhang et al. develop a novel optogenetic tool to induce SG formation rapidly and robustly without the confounding variable of translation repression, allowing them to define the role of SGs in the formation of pathogenic ALS-type cytoplasmic inclusions.
Tools and Key Findings:
Zhang et al. replace the dimerization domain of G3BP1 (a core protein of SGs) with the dimerization domain from cryptochrome 2 (CRY2 – a blue light-absorbing photosensor from Arabidopsis thaliana), thereby allowing rapid assembly of SGs in response to blue light. Importantly, these light-induced granules (named OptoGranules) contain polyadenylated mRNA as well as every canonical SG protein tested, indicating that they are, in fact, bona fide stress granules.
Zhang et al. Supplementary Video 2: Opto-G3BP1 forms granules
upon activation by blue light.
Critically, the formation of OptoGranules DOES NOT involve general translational repression via eIF2⍺ phosphorylation, thereby eliminating the major confounding variable involved in the study of the biological consequences of SG formation. In addition, OptoGranules form within seconds of induction by blue light, and disassemble within ~5 minutes once the light stimulus is withdrawn. The OptoGranules also provide evidence for a definite hierarchy within the SG proteome. While G3BP acts as a nucleator of granules, other canonical SG proteins, such as TIA1, FUS and even TDP-43, are unable to serve as initiators of SG assembly, and are likely client proteins.
With this tool in hand, the authors examine the consequences of chronic, intermittent SG formation. They use a blue-light treatment regime forcing cycles of OptoGranule assembly-disasembly, mimicking chronic stress cells might face within the context of an organism. The OptoGranules formed at the beginning of this regimen contain TDP-43, but not in the hyper-phosphorylated form seen in the pathological ALS inclusions, indicating that they are canonical SGs. However, when cells are subjected to this pattern of OptoGranule assembly and disassembly for extended periods of time, the TDP-43 incorporated within them becomes increasingly phosphorylated and ubiquitinated, and cell viability decreases, a characteristic of ALS inclusions. While the authors’ initial results are performed in the context of a transformed cell line, they recapitulate their experiments in neurons derived from iPSCs expressing OptoGranule-compatible G3BP1, demonstrating in a neuronal context the evolution of SGs into pathogenic ALS-like inclusions.
Taken together, the authors demonstrate that the chronic assembly of SGs is detrimental to the cell, independently of the distal stressor. Further, they demonstrate convincingly that chronically and intermittently stressing cells (and more specifically, neurons) results in the SGs within them to morph into ALS-like pathological inclusions.
Why I chose this preprint:
The cellular response to any individual stress almost invariably involves the activation and/or repression of a multitude of pathways and mechanisms. Inferring a causal chain by deconvoluting the various pathways the cell uses to adapt and survive remains a challenge. In the case of ALS-FTD, a link between SGs and the pathological inclusions had long been suspected, but never proven, due to the confounding variables described above. I found the approach taken by the authors to develop a tool to remove the confounding variable and allow the study of SGs in isolation to be an extraordinarily elegant experimental system. The power of this system was demonstrated in the establishment of a concrete link between SG dynamics and ALS pathology, viz. the evolution of SGs into phosphorylated/ubiquitinated TDP-43 containing pathological cytoplasmic inclusions under chronic stress.
Open questions and future directions:
The authors speculate that physiological amyloid-like states in SGs could serve as ‘seeds’ for the formation of TDP-43 pathological amyloids under chronic stress. One open question that remains is the context and mechanism of TDP-43 phosophorylation. Is TDP-43 phosphorylated during, or as a consequence of, SG incorporation and subsequent amyloid formation? Or does the phosphorylation occur extra-granularly, and promote amyloid formation?
Additionally, given that global translation is presumably not downregulated upon OptoGranule formation (as evidenced by the lack of eIF2⍺ phosphorylation, I would be curious to know whether the Optogranules recapitulate the translationally null state of endogenous SGs.
Broadly, the OptoGranule system offers a marvelous opportunity to further study modulators of SG assembly, dynamics and the biological roles played by this phase-separated cytoplasmic organelle. More specifically, the tool provides an assay to test the roles of various ALS-associated mutations on the formation of the pathological cytoplasmic inclusions. Understanding these mechanisms is critical to inform future efforts to slow or even reverse disease progression.
References:
- Ling, S.C., M. Polymenidou, and D.W. Cleveland, Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron, 2013. 79(3): p. 416-38.
- Aulas, A. and C. Vande Velde, Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS? Front Cell Neurosci, 2015. 9: p. 423.
- Figley, M.D., et al., Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics. J Neurosci, 2014. 34(24): p. 8083-97.
- Youn, J.Y., et al., High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Mol Cell, 2018. 69(3): p. 517-532 e11.
- Buchan, J.R. and R. Parker, Eukaryotic stress granules: the ins and outs of translation. Mol Cell, 2009. 36(6): p. 932-41.
(1 votes) Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the biochemistry category:
Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia
Gustavo Stelzer, Marcus Oliveira
Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice
Gustavo Stelzer, Marcus Oliveira
Notch3 is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart looping
Bhaval Parmar
Also in the cell biology category:
Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancer
Teodora Piskova
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Leukocytes use endothelial membrane tunnels to extravasate the vasculature
Felipe Del Valle Batalla
Also in the molecular biology category:
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
Also in the neuroscience category:
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates
Vanessa Ehlers
Circadian modulation of mosquito host-seeking persistence by Pigment-Dispersing Factor impacts daily biting patterns
Javier Cavieres
Also in the pathology category:
Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer
Simon Cleary
LINC complex alterations are a hallmark of sporadic and familial ALS/FTD
Megane Rayer et al.
Hypoxia blunts angiogenic signaling and upregulates the antioxidant system in elephant seal endothelial cells
Sarah Young-Veenstra
preLists in the biochemistry category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
Peer Review in Biomedical Sciences
Communication of scientific knowledge has changed dramatically in recent decades and the public perception of scientific discoveries depends on the peer review process of articles published in scientific journals. Preprints are key vehicles for the dissemination of scientific discoveries, but they are still not properly recognized by the scientific community since peer review is very limited. On the other hand, peer review is very heterogeneous and a fundamental aspect to improve it is to train young scientists on how to think critically and how to evaluate scientific knowledge in a professional way. Thus, this course aims to: i) train students on how to perform peer review of scientific manuscripts in a professional manner; ii) develop students' critical thinking; iii) contribute to the appreciation of preprints as important vehicles for the dissemination of scientific knowledge without restrictions; iv) contribute to the development of students' curricula, as their opinions will be published and indexed on the preLights platform. The evaluations will be based on qualitative analyses of the oral presentations of preprints in the field of biomedical sciences deposited in the bioRxiv server, of the critical reports written by the students, as well as of the participation of the students during the preprints discussions.
| List by | Marcus Oliveira et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
| List by | Nándor Lipták |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Also in the cell biology category:
November in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
| List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the molecular biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Also in the neuroscience category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
| List by | Alex Eve |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
| List by | Alex Eve |
Also in the pathology category:
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
COVID-19 / SARS-CoV-2 preprints
List of important preprints dealing with the ongoing coronavirus outbreak. See http://covidpreprints.com for additional resources and timeline, and https://connect.biorxiv.org/relate/content/181 for full list of bioRxiv and medRxiv preprints on this topic
| List by | Dey Lab, Zhang-He Goh |
1
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |