Proteostasis | DEZERAECOX

Lorne Proteins 2020

Sat, 08 Feb 2020 05:19:01 +0000

Lorne Proteins 2020

If you’ve landed here after checking out my poster , welcome. If you stumbled here by accident, the more the merrier. Either way, thanks for stopping by!

I hope you found something interesting or useful, and enjoyed hearing about the work we are doing to develop new tools for measuring proteostasis. If you have any questions, want to know more about what we do, or simply want to get in touch, you can find me on twitter head over to the .

For anyone who wasn’t at the conference, or didn’t get a chance to say hi, I have included a brief run-down (and tried to skip over most of the gory – boring, technical – details!).

What’s all this proteostasis business?

Cells have an extensive quality control network responsible for maintaining their molecular machines, including synthesis, folding, degradation and transport

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. Collectively, this machinery is known as the proteostasis network. Proteostasis imbalance results in protein misfolding and aggregation, the central molecular signature of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

We lack knowledge of which proteins in the cell become vulnerable to improper folding during proteostasis imbalance. One measure of protein foldedness is the extent to which a protein can be unfolded thermally or with a chemical denaturant such as urea. Until recently, it has been difficult to track foldedness in cells due to sheer complexity of the many ten’s of thousands of proteins and proteoforms needed for our cells to function.

To overcome this, this work specifically aimed to:

Devise a chemical biology and proteomics approach to monitor the foldedness of the proteome.
Determine the influence of pharmacological agents that unbalance proteostasis on proteome foldedness.

What is tetraphenylethene maleimide, other than a tongue twister?!

Tetraphenylethene maleimide (TPE-MI) is a dye (tetraphenylethene maleimide) that becomes fluorescent when it binds to reactive thiol residues

\[2\]

. Buried, reactive thiols are the most buried residue of all amino acids in globular (properly folded) proteins. Monitoring the exposure of these thiols using TPE-MI gives us a sensitive way to probe foldedness in complex mixtures.

To test this strategy, we used a purified, well-studied protein – β-lactoglobulin. We know both the sequence and 3D structure of this protein, and its behaviour in a range of denaturants is known. β-lactoglobulin has 5 thiol residues, of which two pairs are bonded and the remaining one (Cys121) is buried in the core of the folded protein. As β-lactoglobulin unfolds in increasing concentrations of denaturant, we get a corresponding increase in TPE-MI fluorescence.

But what about the giant protein soup our cells make, I hear you ask…

While TPE-MI can reliably tell us about the unfolding of a single, purified protein, our cells are jam-packed with thousands of copies of thousands of different proteins. How can we possibly know which proteins TPE-MI is binding to?

Enter: proteomics. This revolutionary tool is a workflow based on mass spectrometry which can report back on the composition of complex mixtures – both which proteins are present, and the relative amount of that protein. The basics of this technique are beyond the scope of this post, but if you are looking for more details check out the resources section below

\[3-5\]

. I have included a brief explanation of the method we use below, which relies on isotopically labelling cells in culture before lysing, denaturing and labelling with TPE-MI. Proteins are digested (chopped up) into regular, smaller pieces before analysis via mass spectrometry.

Using custom software, we can identify and quantify protein pieces. Unfortunately, we cannot identify the protein pieces specifically labelled with TPE-MI, but instead, we look for the loss of those pieces. We can do this for many many proteins and start to understand the concentration at which specific proteins unfold. We can even start to understand intricacies in unfolding for separate protein domains.

How does this help us understand disease mechanisms?

This new method now provides a way to monitor how the stability of proteins (measured how much denaturant it takes to unfold them) changes under conditions of proteostasis impairment that are present in disease. For example, we are now investigating the changes in proteome foldedness when we inhibit hubs of the proteostasis network such as molecular chaperones. How do the proteins that rely on specific molecular chaperones to be folded change when those proteins are no longer active? What if we stop the cell from degrading old proteins? Or from decorating their proteins with extra modifications that mediate structure and activity like phosphorylation? Defects in this machinery are common in neurodegenerative protein aggregation diseases and we now have the tools to start tackling these questions.

References and handy links

Chiti F, Dobson CM (2017) . Annu Rev Biochem 86: 27–68.
Chen MZ, Moily NS, Bridgford JL, Wood RJ, Radwan M, Smith TA, Song Z, Tang BZ, Tilley L, Xu X, Reid GE, Pouladi MA, Hong Y, Hatters DM (2017) . Nat Commun 8: 1–10.
Lottspeich, F. (2009). . In Proteomics (pp. 3-10). Humana Press.
Graves, P. R., & Haystead, T. A. (2002). . Microbiology and molecular biology reviews, 66(1), 39-63.

That’s all from me for now. Still can’t get enough or want to know more? Simply want to get in touch? Find me on twitter head over to the - love to hear from you! Now, back to the beach 🏄🌴☀️ !

Toolbox Talk: Scientific posters

Tue, 30 Jul 2019 10:39:57 +0000

Going to a large, often international, conference jam-packed with superstars in your field is one of the privileges of being a scientist. Conferences are essential for building your network, keeping up-to-date with the progress inside your niche and more broadly in your field, and establishing or maintaining collaborations. If you’d like to know more about my conference experiences, check out . I was lucky enough to attend and present short talks at a few conferences in 2017, and it was a wonderful opportunity to show the scientific community what I have been working on.

However, there are only so many oral presenter slots available at such events, and often these are used by the organising committee to highlight the very best and newest science. But what about the rest of us? It can be really difficult to get the most out of a conference, especially as a student, if you don’t have an opportunity to showcase your work. Enter: poster presentations.

Wait, like in elementary school?

If you are thinking of a giant piece of butcher’s paper, covered with scribbles in multi-coloured permanent markers, you aren’t too far wrong. But things have evolved a little since the school days, and we do have slightly more developed tools for displaying our work these days. Unfortunately, making an engaging scientific poster is often not something we are formally prepared for during our scientific training. We are being moulded into the next generation of scientists, after all - what no one tells you is that artist is just one of the many additional hats that you will wear often as your career progresses.

With this in mind, I thought I would share a little about my process and tools for making an engaging poster. It is by no means a one-stop-shop, as every time I make a new poster I learn a little more about the process, but hopefully, you will find something useful as you prepare for that next science-filled conference adventure.

Tools

There are plenty of purpose-built design software packages out there specifically for making commercial posters, and some even targetted at producing scientific visuals. I have included a few links in the additional resources, but to be honest, I have had mixed success with these - if you find any that I have missed or that you’ve found particularly helpful to let me know!

In the meantime, I have settled on a combination of a freely-available vector graphics program (Inkscape) for compiling individual panels into standalone figures and presentation software (e.g. or ) for the overall poster design. If you haven’t heard of vector graphics programs before, or are unsure why you might want to use one, you can read more . In essence, because of the way they are constructed, vector graphics are easy to manipulate and can be scaled indefinitely without losing their quality as they are not composed of pixels, in contrast to the raster-based file types jpeg and png.

For data-laden figure panels, I will usually stick with python or (if you are interested in this, check out some of my other toolbox posts ). For any work dealing with protein structure, is your friend. The learning curve can be quite steep (I am only just now mastering the basics of opening a structure file, editing the colours and changing the display type from ball and stick to ribbon!) but it is relatively easy to produce a striking visual that will aid in any handwavy descriptions of a protein’s structure. Keep an eye out for my beginner’s basic guide to PyMol in a future Toolbox Talk!

Last, but definitely not least, I use a to create a link to this website. Even if the name is not familiar, I am sure that you would have come across in the wild before - they are a type of matrix barcode that links to a website or application when scanned with a smartphone camera. There are plenty of free online platforms for creating your own QR codes, and many that give you the ability to adjust the shape and colour of the individual elements, however be careful to know the difference between static (meaning you have no flexibility to adjust where the link directs after printing) or dynamic (that contain an automatic redirect which you can adjust after printing) to make sure you get one that suits your particular needs. I have found this especially handy for posters - by encoding your contact details or link to your website, it is easy for conference attendees to get in touch without having to hastily scribble down your email on their crumbled napkin.

Techniques and tips

Even the most exciting and life-changing data can find itself on a poor poster. There are many unwritten (and written) rules for making an engaging and eye-catching scientific poster, and many more experienced people than I have written guidelines and tips, some of which you can find in the resources section below. In any case, I thought I would throw in a few of my trusty tips here:

Layouts should be simple and easy to follow. I find that creating boxes to guide the reader through the poster in a logical fashion can be helpful. Remember a poster is about walking someone through your science and stories that jump backwards and forwards can make it hard to stay engaged. As a general rule, try not to require your audience to do too many optical gymnastics to follow the narrative of your science. When creating a new poster from scratch, I like to sketch out the layout, brief text tidbits and figure ideas by hand in A4 format to help get a handle on what data I need to track down and figures I need to produce. I also find drafting this initial layout in A4 size helps to keep my final poster from getting too overcrowded.
Find SVG versions of logos for the institutes that contributed to the work. It is good practice to acknowledge the financial support any project receives, and posters are no exception. In practice, I typically will have anywhere from 1 - 3 logos on my poster and any additional smaller contributions can be acknowledged in the text if you feel it is necessary. I will always find SVG versions of the logos, such that they can be edited and resized without losing any quality. Generally, you will be able to access these from your University brand team, or a quick google search with an advanced filter to find SVGs works well too.

Never underestimate the power of a good colour scheme. There is nothing worse than a poster that looks more like a rainbow kaleidoscope than a scientific document. Try to steer clear of elaborate colour schemes, and away from anything too light or bright. Also, keep in mind that picking a simple colour scheme to use throughout the entire poster (e.g. one type of sample is the same colour in all panels) helps to provide continuity for your reader. For those who are colour-coordinator challenged, a quick google search for colour palettes will provide all the inspiration you need.

Remember the power of size, shape and colour for drawing attention. With the limited time and large amount of information available at poster sessions, conveying the most important points from your work is crucial. Using accent colours, bold fonts or larger sizes can help to draw your reader’s eye to the key aspects of your work, and hopefully prompt them to ask more about the details!
Consistency is key. A poster, aside from displaying scientific results and information, is at the end of the day a piece of art. As with any beautiful artwork, the little things matter! Use the handy aligning and specific dimension setting functions in powerpoint to make sure everything is balanced and consistent. Check that the text sizes, fonts, line widths etc are identical throughout your poster, especially for things like headers and panel outlines. There will always be one or two typos that sneak past you, but it’s also a good idea do several final read-throughs to check for typos - once your masterpiece is printed, there is no turning back!
Print smaller versions for proofing. Printing an A4 version of your poster is a great way to check for readability and those last-minute alignment or spelling errors. As a general rule, anything that is not readable in this format will not become more-so simply by being printed bigger - remember you want to be able to engage your visitors in conversation, not have them glueing their nose to your poster trying to make out the details!
PDF is your friend. Particularly if you include transparent artwork or special characters, it is good practice to export your poster from powerpoint to PDF before submitting for printing. There are also a few tricks with powerpoint to ensure the quality is maximal, which can be found in the ‘Options’ menu of the dialogue box during export.
Be prepared to print early. Some institutions have their own print services, and these can be a cost-effective way to have your poster printed. I have a lot of experience with Officeworks and have generally been thrilled with their service, although I would recommend visiting a store in person to submit and collect your poster. They will generally give you a test print which is handy to make sure your creation survived the file format change. Regardless of which route you choose, plan to have your poster finalised and printed several days before departure - this way you will have a few days up your sleeve to handle the inevitable curve-balls!

Useful resources

from Animate Your Science has some straightforward tips for layout and content. I will admit to disobeying a few of their “rules” but generally great advice!
Toolbox talk on and the

Did I miss your favourite tool or technique? Find me on or head over to the to tell me more!

Image credits: codytdavis, greyritualstudio, alecuffia and arterbury via

FASEB Protein Aggregation Conference 2019

Sun, 30 Jun 2019 04:29:41 +0000

After a science career spanning a decade without having attended an international conference, I have been fortunate enough this year to speak at not one but two! What follows is a not-so-brief rundown of my second international conference, what I learnt along the way and where I am hoping to take these lessons.

The benefits of a niche, narrow-focused conference

From the very first keynote speaker (shout out to Judith Frydman - what a powerhouse for proteostasis research), it was clear to me that this was going to be different to almost any other conference I have attended in the past. This conference (and in fact, the same is true for most FASEB themes) was very targeted around a single area of biology (protein aggregation), meaning that the talks were all very focused and relevant for all attendees. Indeed, the tight-knit and collaborative nature of this community was exemplified by the fact that each speakers acknowledgement slides listed at least one - normally many - other attendees.

It was so refreshing and heartening to see a dedicated community of brilliant researchers converge around this problem with a singular view to solving the puzzle of disease-associated aggregation. As well as this, there was a broad range of techniques on display and I felt that I left with a fantastic cross-section of the breadth of work being done in the field, both for pathogenic and functional amyloid aggregation, ranging from single-molecule through structural, cellular and whole-organism studies right up to clinical trials. Importantly, plenty of researchers presented unpublished data (presumably due to the diminished need for an extensive background in this audience, who are likely to have seen the speakers published works) that I would otherwise not have seen for many more months/years if the paper is held up during publication.

For me personally, this conference represented the intersection of my PhD work (centred on aggregation of a specific protein) and my current postdoctoral work (focusing more broadly on proteostasis and its role in disease-associated protein aggregation). So much has happened in the field since my PhD and it was pure bliss getting to nerd-out surrounded by like-minded people. I was surprised more than once at the new connections my brain was able to find in this setting. I found that by listening to many perspectives/methods targetting similar biology, it was easier to start to integrate those complex ideas rather than reading the papers in isolation. Aside from this, for the junior attendees like myself this conference made for a fantastic job market, with many lab heads in our field advertising positions.

Lessons learnt

A good and engaging speaker is one who is in tune with the audience, including their level of engagement, and who respects the time of the audience by sticking to their allocated slot.
Aim to engage. In a small group such as this, you will inevitably run into many of the high-profile speakers - maybe even at the breakfast table! - so it is essential to have attended and engaged with their talk. Bonus points for devising an intelligent question to follow up on their presented material!
The “comment and a question” audience member will always elicit a collective groan - don’t be this person!
Conference organisation is no small feat - but inevitably the strength of the organisation team will impact on the general experience. In this case, a lack of confirmed program less than a week out from the conference was not a good sign. Missteps in the organisation led to the chaotic herding of humans to food and coffee breaks and program potluck ensued when the speaking slots were revised on day one of the conference.
Location, location, location: Snowmass was an incredible conference location. A small ski village easing into the break between winter ski and summer hiking seasons, there was plenty of sunshine and a brisk breeze all set in front of a stunning snow-capped mountainous backdrop. A huge highlight of the conference was the relative isolation which, while difficult to travel to and from, heightened the sense of community and connectivity between attendees. Spending time immersed in the location will strengthen your connection to that conference. Snowmass made this particularly easy, with plenty of Springtime hikes, walks and sunshine on display.

The who, what, when and where of woeful wifi - an outstandingly woeful conference internet connection elicited plenty of complaints throughout the week. However, I did feel was more engaged with talks that I might not have otherwise prioritised, as it was much more difficult to multitask with attention-sucking admin jobs like email. While sticking almost 100 researchers in a room for large swaths of the day that does not have reliable internet is probably a recipe for disaster, it certainly supports the age-old adage of ‘unplugging’ during seminars/conferences to be emersed in the research at hand.
Chairing is caring - an experienced chair who takes control of a session, including speaker introductions and managing question time, can have a profound impact on the speakers and attendees. It is not a job that should be taken lightly. It is worthwhile paying attention next time you have the chance to observe an adept chairperson, taking note of the often unseen acts that contribute to a flawless, inclusive and positive conference session.
The diversity debate among question askers - it struck me how often the same group of 5 - 10 people in a room of ten times that many were always the ones to ask questions. I have never taken to the microphone at a conference to ask a question of the speaker. Not due to lack of ideas - I will often have a list of question ready and waiting to be addressed - but I always lack courage in a room filled with ’experts’ and my imposter syndrome keeps my butt glued to the seat. Is this maintained as some kind of PI-ready test you have to pass? Throughout this conference, I ruminated on the idea of how to engage people other than those that are brave enough to take to the microphone - there are plenty of free crowdsourcing options out there ( and to name a few), and yet I have not seen a single conference where this is adopted. I am keeping a keen eye open for an opportunity to put this inclusivity initiative into action.
By far the biggest take home from this conference was that everything which seems so significant before leaving for the conference (poster prep, student meetings, experiments, slides, …) will no longer be so important once you arrive, and will be overcome by things like remembering faces of people you meet, feeling comfortable in a room of strangers, testing the confines of your comfort zone and nailing your two-minute “who I am” pitch. I am still working on perfecting these aspects of conference attendance!

Personal perspectives

“Growing a pair” is a lifelong process: it is important to make the most of opportunities at a conference (which can often be once-in-a-lifetime combinations of people, place and perspectives) while understanding and appreciating your limits.
Finding your people and your place: while engaging with diverse people is a key goal of attending any conference, recognising that you need smaller groups and its OK to need more relaxed time (e.g. spending time with small group of colleagues for drinks at a local bar instead of the crowded networking events.

The psychology of ideas: you know that feeling when your idea is discussed during a meeting, and the academic goes on to believe it was theirs? For the first time ever, a senior academic articulated to me their inability to discern where an idea comes from, and it was enlightening. In contrast to my previous reactions, this wisened academic encouraged me (and the other early career researchers present) to hold firm when this happens and to realise that it is most often without malice but simply a product of the multitude of ideas and meetings senior researchers attend every day.
The importance of a mentor in science: it’s no secret. In fact, any time I have spoken to an academic about their career path and trajectory they speak constantly about the different mentors that smoothed their journey. But this conference, I spent a bit of time reflecting on the importance of proactively approaching search for good mentor-mentee relationships. Having mentors that enter your career organically is important, but you should also identify and target strategic additions to your ’team’ of mentors.
Who am I? Every successful and prominent researcher to take the stage at this conference began with “My lab works on…”. It is important to define this early on, and I am very aware of this hole in my current career focus.
The value of contemplation: Conferences have been one of the few times this year that I have taken the chance to sit and think - really think - about science (and life and decisions). While I would like to bring more of this deep contemplation to my every-day science, I am learning to accept and expect these events to be heightened moments of reflection and embrace the soul-searching mood!
Trading hats: with a few days set aside before and after the conference for travel, it was incredible to put on my long-lost tourist hat and enjoy the sights, sounds, smells and sensations of being in a new country. This experience reminded me of how lucky I am to have the opportunity to do this as an academic, and that I should more often take time to reflect on that privilege.

Overall, this conference was a tour-de-force of world-leading experts and cutting-edge research, and included several abstract-selected talks from ECRs (including myself!) that together comprised a diverse and wellbalanced program in a stunning location. Were you in Snowmass this June? Get in touch via and let me know what you thought of the FASEB Protein Aggregation Conference!

Banner image credits:

#LorneProteins2019 & #FASEB2019

Mon, 11 Feb 2019 06:07:09 +0000

If you’ve landed here after checking out my poster or the , welcome. Thanks for stopping by!

Just can’t get enough of the pretty pretty science? You can find details about the work I presented on my poster here. For anyone who wasn’t at these conferences, or didn’t get a chance to say hi, I have included a brief run-down (and tried to skip over most of the gory - boring, technical - details!).

Now - onto the science!

Setting the scene.

Cells have an extensive quality control network responsible for maintaining their molecular machines, including synthesis, folding, degradation and transport

\[1\]

To overcome this, this work specifically aimed to:

Devise a chemical biology and proteomics approach to monitor the foldedness of the proteome.
Determine the influence of pharmacological agents that unbalance proteostasis on proteome foldedness.

What is tetraphenylethene maelimide, other than a tongue twister?!

Tetraphenylethene maelimide (TPE-MI) is a dye (tetraphenylethene maelimide) that becomes fluorescent when it binds to reactive thiol residues

\[2\]

To test this strategy, we used a purified, well-studied protein - β-lactoglobulin. We know both the sequence and 3D structure of this protein, and its behaviour in a range of denaturants is known. β-lactoglobulin has 5 thiol residues, of which two pairs are bonded and the remaining one (Cys121) is buried in the core of the folded protein. As β-lactoglobulin unfolds in increasing concentrations of denaturant, we get a corresponding increase in TPE-MI fluorescence.

But what about the giant protein soup our cells make, I hear you ask…

Enter: . This revolutionary tool is a workflow based on mass spectrometry which can report back on the composition of complex mixtures - both which proteins are present, and the relative amount of that protein. The basics of this technique are beyond the scope of this post, but if you are looking for more details check out the resources section below

\[3-5\]

Using custom software, we can identify and quantify protein pieces. Unfortunately, we cannot identify the protein pieces specifically labelled with TPE-MI, but instead we look for the loss of those pieces. We can do this for many many proteins and start to understand the concentration at which specific proteins unfold. We can even start to understand intricacies in unfolding for seperate protein domains, such as in the example below where different reactive thiols give information on specific domains of Hsp70.

How does this help us understand disease mechanisms?

References and handy links

Chiti F, Dobson CM (2017) Annu Rev Biochem 86: 27–68.
Chen MZ, Moily NS, Bridgford JL, Wood RJ, Radwan M, Smith TA, Song Z, Tang BZ, Tilley L, Xu X, Reid GE, Pouladi MA, Hong Y, Hatters DM (2017) Nat Commun 8: 1–10.
Lottspeich, F. (2009). In Proteomics (pp. 3-10). Humana Press.
Graves, P. R., & Haystead, T. A. (2002). Microbiology and molecular biology reviews, 66(1), 39-63.

That’s all from me for now. Like the pretty pictures? Still can’t get enough of the science? Simply want to get in touch? Find me on twitter or head over the to page - I’d love to hear from you! Now, back to the beach 🏄🌴☀️ or the snow-covered mountains 🏔️⛷️!

Magnified 2018

Tue, 05 Jun 2018 07:53:54 +0000

The Illawarra Health and Medical Research Institute (IHMRI), in association with the School of Arts, English and Media at the University of Wollongong (UOW), are hosting a fundraising exhibition featuring images from the work of researchers and students, in support of Motor Neuron Disease (MND) research at IHMRI. This is a cause quite close to my heart, and as an alumnus, I was lucky enough to be invited to contribute. I actually had a heap of fun choosing my artwork (you can check out my submissions below) and for all the details on when and where you can find the exhibition head . Works in the exhibition will be on sale to the general public, with all proceeds going towards Motor Neuron Disease (MND) research at IHMRI. What better reason do you need to pick up some fantastic sciart?

Decoding Proteostasis

Proteins are the major cellular building blocks fundamental for most basic operations sustaining life. Most proteins need extensive management by the cell’s proteostasis machinery to maintain their proper shape. Proteostasis imbalance can cause neuronal death, leading to neurodegenerative disease. Various cellular stresses, such as inhibiting housekeeping functions or dismantling structural components, can differentially impact neuronal health. Understanding changes in each individual protein (columns) within a cell as it responds to different stresses (rows) highlights how different stress types influence proteostasis. Revealing common vulnerable pathways, by decoding this ‘proteome barcode’, will help focus future therapeutic targeting on neurons weakest links.

The twists and turns of proteostasis

Misfolded proteins aggregate into elongated fibrils (yellow/green ribbons), which cause neuronal death and lead to neurodegenerative diseases like MND, Parkinson’s and Alzheimer’s disease. Using powerful microscopes, we can watch how the molecular chaperones (red), part of the cells proteostasis defence network, attach along the fibrils, helping to protect the neurons from these toxic tentacles.

Manuscript: The sticky cell savers

Wed, 14 Mar 2018 09:01:25 +0000

All great wines and whiskys are matured, some for many many years. Ageing in this way allows time for complex chemical interactions that improves their quality. Although the maturation process for my latest scientific publication wasn’t quite as long as a quality (traditionally 12 - 21 years, in case you were curious), there were times where it felt as though I was never going to get to crack open the barrel! But, we are - and with that, the remainder of my PhD research is finally published.

I will do my best to not bore you with the details, and instead try to distil 4 years of research, experiments, writing, revisions, more experiments and more revisions into a succinct description of why this paper is important. But first, if you haven’t already found it, I recommend looking here for a little context.

AIM: To examine the ability of the small heat shock molecular chaperone proteins to interact with higher order aggregates (oligomers and fibrils) of alpha-synuclein, whose aggregation is associated with Parkinson’s Disease.

NOTABLE METHODS: Single molecule total internal reflection fluorescence (TIRF) microscopy - allows us to visualise directly the chaperone proteins interacting with fibrillar alpha-synuclein, reactive oxygen cell toxicity assay to monitor the impact of fibrillar alpha-synuclein on live cells in the presence and absence of chaperone.

THE BEST BITS: Directly visualising the interaction between a small heat shock molecular chaperone protein and alpha-synuclein fibrils. While this wasn’t the version that made it into the manuscript, it’s one of my personal favourite science images so far!

TIRF image of fibrils (blue, green, yellow), with bound chaperone (red)

TAKE HOME MESSAGE: Small heat shock proteins have multiple mechanisms of interacting with potentially toxic proteins. These molecular chaperones are well-suited to intervening at various stages in the aggregation pathway to protect cells from toxicity.

If you’d like to read the full article, or maybe check out a few more pretty pictures, you can find it .

lifeguards of the cell

Sun, 11 Mar 2018 09:39:27 +0000

I believe communicating science with a broad and diverse audience is our responsibility as researchers. One of my most important audiences has always been my friends and family, many of whom didn’t do or don’t remember a single high school biology lesson. Needless to say, they’ve been a great testing ground for honing my elevator pitch - and I’ve discovered a neat metaphor makes it so much easier to describe complex scientific concepts without the dumbfounded look that normally accompanies any mention of protein homeostasis at family BBQ’s. Thankfully, our beach side home of Wollongong provides plenty of inspiration!

My scientific passion is understanding how each cell in our body achieves the world’s greatest balancing act - keeping all of its basic building blocks, proteins, in their correct three-dimensional conformation and therefore a functional state. Cells have an intricate network of ’lifeguards’, the proteostasis network, who monitor the proteins (or swimmers), keeping them folded and active or sending them to be degraded when they are no longer functional or needed. When there are disruptions to these lifeguards, the swimmers begin to drown (misfold) and can take others down with them (non-functional proteins accumulate) - at which point our cells begin to die. In the case of neurons, this cell death manifests as diseases like Alzheimer’s, ALS and Parkinson’s disease. It is therefore immensely important for us to understand why proteins begin to drown, how the lifeguards work and what contributes to their failure.

Much of my PhD work centered on one type of lifeguard - the small heat shock molecular chaperones. These lifeguards essentially patrol the beach, watching the swimmers, and spring into action when they detect a swimmer in trouble (a misfolded protein). Unfortunately they don’t have the ability to completely rescue a drowning swimmer (refold the protein), but they are quite good at bringing them back to the clubhouse and keeping them safe until help arrives (holding the protein in a folding-competent state). I focused my research on understanding how the small heat shock proteins help the swimmers (do they give them a life-ring? a pair of floaties? when do they hand them over to the experts?), and whether there was anything they could do once the drowning swimmers started to accumulate.

As a result of my PhD research, we now know that there are many ways the small heat shock proteins can interact with a particular type of swimmer (a-synuclein, whose misfolding and accumulation leads to Parkinson’s disease). Understanding these fundamental mechanisms is a crucial step in developing therapeutics to target the cellular lifeguards, to help treat or cure the diseases that result from their failure.