Proteostasis Design Competition 2024

PROTEOSTASIS

Design Competition Entries

"This booklet showcases the entries to the Babraham Institute Proteostasis Design Competition. The range of posters and artwork developed by students is fantastic to see.

Peter Rugg-Gunn, Head of Public Engagement Babraham Institute

The thought, creativity, and research that has gone into all of them is evident to see. A huge thank you to all everyone who has shared their work!"

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CONTENTS

Nutrient-Sensing Pathways Regulating Autophagy in Proteostasis

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Surface Proteins

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Danielle |Beaulieu Convent School

Romaisa H | Westcliff High School for Girls

Structural proteins across the kingdom

Proteostasis 4

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Alexa M | Sir John Lawes School

Ellen | Beaulieu Convent School

Dysregulation Cutis Laxa

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Leona | Beaulieu Convent School

Iona | Beaulieu Convent School

Building Connections The link between Proteostasis and Cancer: Leveraging AI to track and analyse effects

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Amira B | Hills Road Sixth Form College

Untitled

Izzy | Beaulieu Convent School

Proteostasis: The key to cellular stability 7

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Malikai S, Cardiff Sixth Form College, Cambridge

Sophia | Beaulieu Convent School

Scarface

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Hannah | Beaulieu Convent School

Untitled

8 The right proteins in the right place

Danielle | Beaulieu Convent School

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Danielle | Beaulieu Convent School

Stress and its impact on age-related diseases

9 Proteostasis and Cancer

Jasmine T| Hills Road Sixth Form College

Shingles Iona | Beaulieu Convent School

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Vincent C | Cardiff Sixth Form College, Cambridge

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Central Dogma

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Hannah | Beaulieu Convent School

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Nutrient-Sensing Pathways Regulating Autophagy in Proteostasis

By Romaisa H, Westcliff High School for Girls Introduction Proteostasis, or protein homeostasis, refers to the delicate balance of protein synthesis, folding and degradation necessary to maintain cellular function and health. Proteostasis is essential for cell survival, as even minor disruptions can lead to protein aggregation, cellular stress, and ultimately, disease. Autophagy is a cellular recycling process and a key part of the proteostasis network, breaking down damaged proteins and organelles to prevent toxicity and support cellular resilience. This process is carefully regulated by nutrient-sensing pathways like mTOR and AMPK, which respond to nutrient and energy levels in the cell, adjusting autophagy as needed. Targeting these pathways could enable therapies to boost autophagy in diseases where proteostasis fails, such as in neurodegenerative disorders, including Alzheimer’s disease.

The Role of Autophagy in Proteostasis Autophagy, meaning “self-eating” in Greek, describes the process by which cells engulf and break down their own components. During autophagy, unwanted components are engulfed in vesicles, degraded by lysosomes, and repurposed, which supports proteostasis by preventing toxic buildup.

Macroautophagy: The most common type, where large cellular components are enclosed in a double-membrane vesicle (autophagosome) and delivered to the lysosome for degradation Chaperone-Mediated Autophagy (CMA): Selective type where specific damaged or misfolded proteins are identified by chaperone proteins and directly transported across the lysosomal membrane for degradation

Nutrient-Sensing Pathways and Their Impact on Autophagy Several nutrient-sensing pathways regulate autophagy in response to the cell’s metabolic needs.

This dynamic regulation ensures cells can adapt to changing environmental conditions, preserving protein health and overall cellular function. mTOR: Activated in nutrient-rich conditions, suppresses autophagy to allow for cell growth and protein synthesis AMPK: Activated during low energy or nutrient stress, promotes autophagy to conserve resources and maintain energy balance SIRT1: Responds to cellular stress and energy levels, enhancing autophagy to support protein quality control and cell survival

Evidence of Poor Nutrient Sensing in Alzheimer’s Disease An important study on the role of autophagy in AD by Nixon et al. (2005) found increased autophagosomes in the frontoparietal cortex of patients using immuno-electron microscopy (Figure 1). A study by Pickford et al. (2008) showed that Beclin-1, a protein that plays a central role in autophagy, is significantly reduced in AD brains. Additionally, autophagy-regulating genes like PICALM are linked to tau accumulation, forming neurofibrillary tangles in model organisms such as zebrafish and Drosophila (Moreau et al., 2014). Overactivation of mTORC1 signaling, an amino acid sensing pathway, is also associated with increased amyloid-beta accumulation, while inhibiting mTOR reduces amyloid-beta levels (Kioussis et al., 2021; Caccamo et al, 2010). These findings underscore the potential of targeting autophagy and nutrient-sensing pathways as strategies to mitigate protein aggregation and slow AD progression.

Solutions ●mTOR inhibition: Rapamycin has shown promise in animal models of AD. By inhibiting mTOR, rapamycin activates autophagy, leading to enhanced clearance of Figure 1 - “Ultrastructural amyloid-beta. appearance of autophagic AMPK activation: vacuoles in AD brain and highly purified subcellular fractions from AMPK promotes autophagy under low-energy mouse liver” by Nixon et al.

(2005) conditions. Metformin has been studied for its ability to enhance clearance of protein aggregates in neurodegenerative models

Conclusion: How does this inform future directions in proteostasis research?

Nutrient-sensing pathways, particularly mTOR and AMPK, are essential for regulating autophagy, a cellular process critical to proteostasis, which is often disrupted in neurodegenerative diseases. In conditions like Alzheimer’s, impaired autophagy leads to toxic protein buildup and cellular stress, but modulating these pathways offers a promising strategy to mitigate these effects. Overall, the field has made significant progress in uncovering the dynamics between autophagy and proteostasis but there are still many unanswered questions worthy of further study.

References Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nature reviews Drug discovery.

2012;11(9):709-730. doi:https://doi.org/10.1038/nrd3802 Ondaro J, Haizea Hernandez-Eguiazu, Maddi GarciandiaArcelus, et al. Defects of Nutrient Signaling and Autophagy in Neurodegeneration. Frontiers in Cell and Developmental Biology. 2022;10. doi:https://doi.org/10.3389/fcell.2022.836196

Nutrient-sensing pathways regulating Autophagy in Proteostasis Romaisa H, Westcliff School for Girls

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Structural proteins across the kingdom Ellen , Beaulieu Convent School Animals don’t have cell walls. We rely on proteins to keep our body shapes, from skeletons to butterfly wings.

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Cutis Laxa Iona , Beaulieu Convent School The protein elastin is essential across our body, from allowing arteries to stretch as blood surges through them to allowing our skin to move as our musculoskeletal systems does. However this protein and its connections can be affected by illnesses as well as genetics. We often see the external effects first as skin sags alerting healthcare professionals to the dysregulation of elastin function.

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The link Between Proteostasis And Cancer: Leveraging AI To Track And Analyse Effects Amira B, Hills Road Sixth Form College 1. Background

Main experiment

Proteostasis is the mechanism that maintains the balance of protein synthesis, folding and degradation in cells [1] ❖ It is crucial to cellular function and overall health.

Part 1: All participants will be exposed to the proteosome inhibitor- Bortezomib

Studies have suggested that cancer cells thrive on proteostasis [3] [1]: ❖ They modify proteostasis pathways to support rapid growth ❖ and ❖ survival Upregulation of molecular chaperones to enhance protein folding and prevent aggregation Activation of the unfolded protein response

Part 2: Data collected from the therapy will be fed into the supervised ML model

Proteasome inhibitor: Bortezomib

Supervised machine learning model

Therpeutic targeting [5]: ❖ Increased proteasome inhibitors like bortezomib in multiple myeloma can selectively target cancer cells highlighting their vulnerability to proteostasis distruption AI has been found to be a useful tool in research related to

Figure 1: AI tracking proteostasis differences in healthy vs cancerous cells

proteostasis and cancer, for example [4]: ❖ It has revolunionised the prediction of protein structures ❖ with high accuracy Help identify mutations that alter folding and how these changes can drive cancer

2. Research questions RQ1: How can proteostasis impact the development of cancer?

RQ2: To what extent can cancer be eliminated by means of therapeutic targeting using proteasome inhibitor Bortezomib?

RQ3: To what extent is AI useful in tracking the effects of proteasome inhibitor Bortezomib in cancer?

3. Methodology ➢ Participants aged 18-40 ➢ 100+ participants in each category

4. Expected Outcomes and Implications Anticipated findings: ❖ Some sensitivity in cancer patients with regular proteostasis ❖ due to the distruption of normal protein degradation Higher efficacy is expected in cancer patients with enhanced proteostasis due to increased reliance on proteosomal degradation more pronounced than in patients with regular proteostasis potentially leading to cell death ❖ Minimal or mild response in the control group Impact: efficacy validates proteostasis pathways for ❖ Significant ❖ cancer therapy development of more drugs More personalised treatment strategies

References: [1] Labbadia, J., & Morimoto, R. I. (2015). Proteostasis and cancer: emerging concepts and therapeutic targets.Journal of Biological Chemistry, 290(32), 18703–18711.https://www.jbc.org/article/S00219258%2822%2900370-2/fulltext [2] Hipp, M. S., Park, S.-H., & Hartl, F. U. (2014). The proteostasis network and its decline in ageing.Nature, 509(7501), 451– 460.https://www.nature.com/articles/nature20144 [3] Davenport, A., & Torres, P. (2020). Proteostasis in cancer: emerging therapeutic opportunities. InCancer Therapeutics: Challenges and Opportunities(pp. 50–67). Springer.https://link.springer.com/chapter/10.1007/978-3-030-38266-7_4 [4] DeepMind. (2020). AlphaFold: A solution to a 50-year-old grand challenge in biology.Nature.

Retrieved fromhttps://www.nature.com/articles/s41586-020-03163-7 [5] Adams, J. (2004). The development of proteasome inhibitors as anticancer drugs.Cancer Cell, 5(5), 417-421.

The link between Proteostasis and Cancer: Leveraging AI to track and analyse effects Amira B, Hills Road Sixth Form College

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Untitled Sophia , Beaulieu Convent School

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Untitled Danielle, Beaulieu Convent School

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STRESS AND ITS IMPACT ON AGE-RELATED DISEASES. How stress interferes with proteostasis.

Nowadays, people are more aware of the fact that stress might lead to aging, but are we aware of the reason behind? Today, we will be exploring one of the causes of aging - proteostasis.

Proteostasis, or protein homeostasis, is a complex system of our body that maintains the balance of proteins in terms of synthesis, folding, transport, and degradation. A dysfunction in proteostasis can lead to protein aggregation (which is the misfolding of proteins), which then can contribute to many age-related diseases such as cancer, Alzheimer disease and Parkinson disease.

The heat stress response is triggered by the exposure of stress in eukaryotic cells within the environment.

Research has shown that when HSR is triggered, heat shock proteins (HSPs) which act as molecular chaperons are synthesised. HSP primarily serves a cytoprotective function as they help protect cells from the harmful effects of stress by helping other proteins to fold into their correct shape, allowing them to carry out their function. In cases of protein aggregation, HSPs bind to these misfolded proteins, helping them to refold and therefore protecting cells from the toxic effects of aggregated proteins.However, when these stresses build up, it can lead to protein defect, leading to wide variety of disorders ranging from neurodegenerative diseases to ischemia-reperfusion injury.

The unfolded protein response (UPR) is the maintenance of balanced protein folding in the endoplasmic reticulum (ER) which is responsible for the synthesis and transport of proteins to other organelles. The UPR is activated when unfolded proteins accumulate in the ER. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6.

IRE1 - supports cellular health by reducing stress through adaptive responses, including mRNA splicing and degradation.

PERK - reducing protein synthesis, promoting stress response genes, and triggering apoptosis if stress continues to build up ATF6 - enhances the cell's ability to cope with ER stress by increasing the production of chaperones, promoting protein degradation

This figure shows genetically modified C. elegans worms that expresses a fluorescent reporter for heat shock protein 70 (HSP70).

However, if the UPR fails to reduce unfolded proteins and the UPR signal remains high, it can possibly lead to cell death. A study in “Proteostasis and Aging” shows that stress-induced changes in the endoplasmic reticulum (ER) can cause a 30% increase in protein misfolding, leading to neurodegeneration.

Oxidative stress is caused by the imbalance between free radicals and antioxidants which can sometimes be triggered by infections and over-excercising, etc. With aging, oxidative stress also tends to increase. As a result, the excess free radicals are likely to damage body cells and tissues, specifically lipids and proteins, resulting in the build up of misfolded proteins, which are characteristics in age-related diseases such as Alzheimer disease and Parkinson disease. A study in “Oxidative Stress, Proteostasis and Aging” shows that increased oxidative modifications have been shown to correlate with a 40% decline in proteostasis capacity in aged cells. It can also cause damage to DNA in healthy cells, increasing the chances of cancer.

https://www.nature.com/articles/s41580019-0101-y https://www.sciencedirect.com/topics/me dicine-and-dentistry/heat-shockresponse#:~:text=The%20heat%20shock %20response%20(HSR,the%20proteome %20(Figure%20268.1). https://journals.plos.org/plosgenetics/arti cle?id=10.1371/journal.pgen.1003466 https://pmc.ncbi.nlm.nih.gov/articles/PM C9345296/ https://pmc.ncbi.nlm.nih.gov/articles/PM C8146082/ https://www.researchgate.net/figure/Aut ophagy-decreases-with-age-leading-toloss-of-proteostasis-accumulation-ofprotein_fig3_338582840 https://my.clevelandclinic.org/health/arti cles/oxidative-stress

The figure above shows that as cells age, the efficacy of autopagy and proteostasis decreases, accompanied by the increase in oxidative stress. When these processes decline, damaged proteins can accumulate in cells, disrupting cellular function, increasing chances in various diseases. In conclusion, a positive correlance is shown between stress and age-linked diseases and therefore is important for us to stay aware of the situation and take action early on. It also highlights the importance of proteostasis in our bodies and significance of healthy aging by taking a proactive approach to your health.

Stress and its impact on age-related diseases Jasmine T, Hills Road Sixth Form College

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Shingles Iona , Beaulieu Convent School The same virus that causes chickenpox can lie dormant in neuronal tissue due to a transcript stopping the expression of a gene needed for viral replication. This self-governing proteostasis mechanism on a viral scale can allow the virus to lie dormant for decades, and then blossom as flowers in a garden when conditions are just right.

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Surface Proteins Danielle , Beaulieu Convent School Different cells have different roles to play. They need to be able to recognise each other as safe so not to trigger an immune response, but sometimes the proteins on surfaces can be altered or over-expressed leading to a loss of function or an autoimmune response.

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Proteostasis

by Alexa M Introduction

1) Protein Synthesis

2) Protein Folding

Proteostasis, or protein homeostasis, refers to the cellular processes that maintain protein function, health and stability. It’s essential for cellular function, as proteins play a role in a variety of functions, from providing structural support to catalysing metabolic events.

A cell’s ribosomes link amino acids in an order specified by the genetic code to translate mRNA into proteins.

Errors may occur during the translation process, producing proteins that are incomplete or incorrect for a cell’s function. Under stress, the cell’s ability to regulate the rate and timing of protein synthesis is essential. Certain proteins are synthesised more quickly in response to stress to control/lessen damage, while other synthesis processes may be stopped temporarily to conserve a cells resources. Cells have quality control mechanisms, during synthesis, that recognise and tag incorrectly synthesised proteins for degradation.

Synthesised proteins are needed to fold into specific shapes to function correctly. Proteins, called Chaperone proteins, bind to partially folded proteins to prevent incorrect folding or aggregation (when misfolded/damaged proteins clumps together to form aggregates).

The idea of proteostasis covers protein synthesis, folding, trafficking and degradation (destruction) to prevent disruption to cellular functions.

Certain proteins require enzymatic modifications or cofactors to fold correctly. Some proteins require a complex environment to fold, for example Chaperonin complexes in humans, which provide an isolated environment for folding.

3) Protein Trafficking Folding and post-translational modifications happen in the Endoplasmic Reticulum (ER). The proteins are checked here for quality before the proteins proceed to the Golgi Apparatus. Properly modified and folded proteins are packaged in transport vesicles and are sent to the Golgi Apparatus for further soring and modifications, after which are directed to their function e.g. lysosomes, cell surface etc.

In the ER, there is quality control, where only correctly modified and folded proteins are allowed to move forward in the trafficking pathway.

The proteasome tags and retro translocates misfolded proteins or aggregates out of the ER for destruction.

4) Protein degradation Ubiquitin-Proteasome System (UPS) is the main cell breakdown process.

Ubiquitin molecules bind to proteins that have been tagged to be broken down, guide them to the proteasome, where proteins are hydrolysed into peptides. The UPS is essential to prevent buildup by breaking down damaged or misfolded proteins.

Why is the process beneficial?

Proteostasis is the foundation for cellular longevity and health. Proteostasis lowers the risk of disorders linked to protein aggregation and misfolding, promotes resistance against stress, and slows down the ageing process by controlling the quality and function of proteins

Autophagy occurs when larger aggregates are needed to be broken down. This process involves the packaging of damaged or large aggregates in autophagosomes, which then merge with lysosomes.

Aggresomes are structures that act as short-term storage locations for misfolded proteins that can’t be broken down right away, to reduce the harmful consequences of protein aggregates.

Proteostasis Alexa M, Sir John Lawes School

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Dysregulation Leona , Beaulieu Convent School Our ability to control our emotions pulls on the genetic code and how the environment leads to proteins being made or not. Dysregulation shows how our minds are not always controllable.

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Building Connections Izzy, Beaulieu Convent School Deep within the central nervous system, coordinating neurones need to be able to receive chemical signals from adjacent cells and then send chemical messages out to other cells across synapses. If receptors are down-regulated through over-exposure to stimuli, these cells may become desensitised and not coordinate a response. This piece highlights the zonal expression of different proteins within a bipolar cell. Our ability to learn depends on neurones forming spatial connections with those around them, being held in the right places and in the correct orientation. This requires new proteins to be expressed with polarity, whether these are structural or involved in signalling. As we get older, some of these connections are lost and we struggle to learn new things and remember what we previously knew.

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Proteostasis: The key to cellular stability Malikai S, Cardiff Sixth Form College, Cambridge

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Scarface Hannah, Beaulieu Convent School Following damage our bodies must repair themselves to prevent infection or further damage. Cells close to the injury need to upregulate the proteins involved in repair which as often fibrous proteins. These proteins may be strong, but they put down in such quantities that the tissue changes, it will look different, it will feel different, it is scar tissue.

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The right proteins in the right place Danielle , Beaulieu Convent School Our bodies are full of trillions of cells, each specialised for a particular role.

Cells must be able to express only the correct proteins in order to support our bodies to survive and thrive. If some proteins are over- or under-expressed it could lead to a loss of function or perhaps the loss of regulation leading to cancerous cells dividing uncontrollably.

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Proteostasis and Cancer Vincent C Cardiff Sixth Form College Cambridge

Introduction: What is Proteostasis?

Proteostasis is a regulatory cellular mechanism that helps maintain the stability, folding and degradation of proteins in our cells. Proteostasis is crucial in the prevention of diseases such as cancer, neurodegenerative disorders, and metabolic syndromes.

Proteostasis plays a dynamic role in tumour growth inhibition and progression. Disrupting proteostasis can cause an accumulation of misfolded proteins, which is associated with the mutation of normal cells into cancer cells. However, heat shock and unfolded protein responses (HSR & UPR), which are proteostasis stress responses to misfolded protein accumulation, can promotetumour growth.

This poster will mainly focus on the relationship between proteostasis stress responses and tumour growth.

Tumour by Freepik - Flaticon

Unfolded Protein Response and Tumourigenesis The Endoplasmic Reticulum (ER) is an organelle in human cells responsible for protein synthesis, folding, modification and quality control. ER stress is incurred when the ER becomes overwhelmed and unable to properly fold and process proteins. This can lead to a buildup of misfolded or unfolded proteins, the longer the misfolded proteins and ER stress is present, the higher the chance of tumourigenesis, the formation of malignant tumours.

In humans, the unfolded protein response (UPR) signal pathway is initiated in response to ER stress to maintain proteostasis by orchestrating proper protein folding and degradation of unfolded/misfolded proteins. Surprisingly, UPR has also been discovered to be linked with cancer development, as the UPR is often found to be upregulated in cancer, suggesting that UPRs may serve a tumorigenic-promoting role by increasing the protein folding capacity and prolonging cancer cells’ resistance to anticancer drugs.

Heat Shock Response and Tumourigenesis Like UPRs, heat shock responses (HSRs) assist in proper protein folding and prevent the accumulation of misfolded proteins, maintaining cellular proteostasis and reducing the risk of tumorigenesis. However, there is also overwhelming evidence that HSR is linked to tumourigenesis, with heat shock proteins (HSP) being expressed at high levels in cancers to form fostering environments that are essential for tumour development.

In addition, HSPs also participate in the evolution of cancer treatment resistance.

References 1.

Ojha R, Amaravadi RK. Targeting the unfolded protein response in cancer.

Pharmacol Res. 2017 Jun;120:258-266. doi: 10.1016/j.phrs.2017.04.003. Epub 2017 Apr 8. PMID: 28396092;PMCID:PMC5542584.

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Calderwood SK, Gong J. Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends Biochem Sci. 2016 Apr;41(4):311-323. doi: 10.1016/j.tibs.2016.01.003. Epub 2016 Feb 11. PMID: 26874923; PMCID:PMC4911230.

Proteostasis and Cancer Vincent C, Cardiff Sixth Form College, Cambridge

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Central Dogma Hannah, Beaulieu Convent School For many years we have understood how DNA is transcribed into mRNA which is translated into proteins, but we have only scratched the surface. We are now developing our understanding of how genes are regulated, how mRNA polynucleotides are altered and how polypeptides are twisted and glycolated in different specialised cells.

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Thank you to all those involved in judging the Design Competition : Ian McGough Becky Gilley Amar Soory Ellie Griffiths Sophie Sanford Thank you to Babraham Research Campus for providing the venue for the Babraham Institute Sixth Form Conference, where these design competition entries were displayed.

Thank you to all the guest speakers at this year’s conference: Nick Ktistakis Yoon Hee Choi Nicola Watts Khashayar Khoshrou