2017 Winter Brainwaves Newsletter

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brainWAVES The Newsletter of the Brain Foundation

Winter 2017

Callum's tribute to Jacinta All of our regular supporters would have been aware of a great fundraising effort early in 2016, when Callum Smith of Melbourne, hopped onto his surf ski and paddled, for two days, around the edge of Port Phillip Bay. No mean feat – in fact, quite inspirational from such a young man. Well, Callum decided to do the same again in February this year. His sister has survived the removal of a tumour in her brain stem. But that is only the beginning of her story. Below is Callum’s tribute to Jacinta. It reminds us all of why we do what we do and why you support our efforts. When these obstacles come into your life it can feel so unbecoming. Jacinta’s healing has peeled away at each layer of her identity until it stripped her right down so that she has had to start again. I’ve never told her this but it has been a privilege to witness her build herself up piece by piece over the past two years - she’s faced her own mortality, experienced pain I hope none of you ever have to feel, loss on so many levels. But I don’t think she would change anything. Because she turned the sh…ty experiences into empathy. Challenge you to find a more loyal or caring person. Callum with his support crew from Port Melbourne Life Saving Club 2017

This isn’t the norm for me to share something so personal. But this is important. The ocean has been a place where I have been able to reflect, relax and find solace. I’m lucky to have this place where I can go to feel centre to self. It’s given me so much – and in my opinion built me into a person that I’m proud to be. The past two years – and in reality it has been three years – I’ve watched my sister’s ongoing battle with her spinal cord tumour and debilitating neuropathic pain. If you were to look at her social media profiles or even meet her in person you’d have no idea of what she puts up with every single day. People ask her how the recovery is going and she’ll smile and tell them it is going great and that life is back on track. But really – her recovery has been mental not physical. She lives in chronic pain now – hard to imagine a 25 year old in that state – but it’s the truth. I’ve seen her in tears at 1am because her bedsheets feel like they’re burning her skin. That’s what neuropathic pain is. Its ants crawling under your skin, it’s burning, and its agony when wind hits you.

The reason there isn’t, is simply lack of Funding. It is a simple as that. Brain cancer receives less than 5% of federal government cancer research funding. So whilst awareness is a word said far too often, in this case it is hugely important. I implore you to stand with us to urge the government to put more funding into the areas of brain cancer and neurological disease. And whilst we do this – please donate to the Brain Foundation. No one deserves to die or suffer simply because they don’t have the funds.

She’s not just there for people in their time of need but she is there for the whole ride. She’s stood by people and shown genuine care, even for those you didn’t deserve it.

It can feel as though you’re at a dead end – survival rates for Brain Cancer have not improved over the past 30 years. And it makes ZERO sense that the government are not pulling their weight to help this fight.

October this year (2016) she lost one of her closest friends to brain cancer. Kate Bourke. Kate was a mother, a daughter, a partner, a best friend. She was young, fit – in fact she was an Iron Woman, and supremely funny.

So this February as I undertake this paddle. I do it for not only Jacinta and her late friend Kate but for all those who are warriors in the face of neurological disease.

The other thing with this disease as with so many neurological illnesses is that whilst you are fighting for your life – you are financially drowning. Brain cancer is the most expensive cancer to have. Brain cancer costs more per patient than any other cancer because it is highly debilitating. It affects people in their prime and often means they and family members cannot work if they become carers. You only have to search the internet to see that for those aged between 35-44 brain cancer accounted for the highest proportion of cancer expenditure – totally $32 million. People often ask Jacinta whether she is on pain killers still. It’s a question that for those who have zero idea about her condition would not be aware of how hurtful it can be to ask that. Jacinta is on neuropathic pain killers twice a day. And won’t be able to stop until there is more research and developments into nerve pain.

Sentimentally Kate had the same connection as I did to the ocean. She would swim regularly in the ocean down the peninsula. Often out to a point where no one could see her – even when she was unwell. I do this in memoriam for Kate Bourke. And I’ll be raising money for the Brain Foundation. Jacinta once told me that pain transforms you – you have to learn to accept change even if it is excruciating – you have to stand up when it slaps you down. You’re not meant to be happy all the time. Life can be hard. And challenges happen. Not because you’ve done it all wrong but because it can hurt for everyone. You have to let the obstacles come and leave you with ammunition to move onto the life you were meant to live on this earth. Kate’s family – her mother Carol and mine are determined to push the government to put more funding towards neurological disease.

Contact the Brain Foundation PO Box 579, Crows Nest NSW 1585 Telephone: 02 9437 5967 or 1300 886 660 Email: info@brainfoundation.org.au Visit our websites brainfoundation.org.au and headacheaustralia.org.au

Fabulous Fundraisers Big Trivia – big fun!

Go Fundraise young man –

This year, Brain Foundation launched BIG TRIVIA: a fundraising initiative designed for everyone to organise and enjoy.

A head shave sounds like a great idea!

Coinciding with Brain Awareness Week in March, there were events held in Sydney, Blue Mountains, Canberra, Melbourne and more. The gatherings proved to be very competitive – good to see brains being put to work – and lots of fun! A very big thank you to our 18 fabulous organisers who have raised significant funds for our research programme and a special thank you to the indefatigable Kate Dorrell (katedorrell.com) whose pro-bono time and effort brought the concept to fruition.

Hayden Delos is young man who was faced with some terrible news. His mother has been diagnosed with a brain tumour.

Sophia and Leeroy, Elk & Pea

We commend him for a very impressive result and wish his mother all the very best in her fight.

Impressive Trivia Masters who excelled are:

Cocktails before Sunset

• Sophia and Leeroy – Elk and Pea Restaurant, Canberra • Anirudh Kathirvel – Dingley Village, Melbourne • Kate Dorrell – Glenbrook, Blue Mountains

Anirudh, Dingley Tennis Club

• Bridgeview Hotel – Willoughby, Sydney

To help kick start this wonderful event we thank Aspen and Allergan for their support.

We look forward to an even Bigger Trivial 2018.

In order to raise awareness and to support his mum, Hayden decided to shave his head to contribute to research into this terrible disease.

Host your own event! If you think this sounds like fun, and would like to immerse yourself in the trivia of life, then why not hold your own event. You can do this at any time. We provide all you need to entertain. You provide the brain power for the fun. Please contact our office on 1300 886 660 for all the details.

Cheryl Doyle held her bi annual Cocktail Party last December in memory of her late husband, John, who passed away from a brain tumour. A wonderful entry into the festive season, the whole family is involved in the planning of the event and it is supported by many friends of the family and her late husband. This is a terrible disease that has had no real treatment advances in many years. We thank Cheryl for her continued support for research in this area. Next year, we think we will name a Cocktail after her!

OLI’MPICS in Oz No, that’s not a typo. Oli’mpics is held in memory of a great friend, Oliver Farrell, who tragically passed away from a traumatic brain injury following a hit and run a few years ago. Each year a group of friends get together to hold a sportsday – a series of 7 events to raise money for charity. Sounds like great fun. Having raised over $25,000 in Australia, 2016 was the inaugural year for Brain Foundation. We thank them so much for the support in Oliver’s name. He would be proud.

Cheryl and her family along with Gerald, drawing the raffle

Pharmaceutical Expo Brain Foundation was represented earlier this year at the Pharmaceutical Society of Australia Careers Expo. As a Health Partner, especially in the area of Headache and Migraine, this was a great opportunity for us to get our information out to pharmacists old and new. Thank you Jacinta Johnson for manning the stand so efficiently. The crew at the Oi’mpics fundraising event 2

The Newsletter of the Brain Foundation

Headache Australia Migraine World Summit – April 2017 Did you attend?? With nearly one-in-four households impacted by migraine, the online Migraine World Summit brought together 36 experts from 8 nations to provide answers, advice and current best practice on this debilitating disorder. Tens of

thousands of people from over 150 countries attended, making it the largest headache patient event in the world. Stigma surrounding migraine still remains. Migraine is a genetic neurological disease and many people struggle with isolation, lack of hope and impact to their physical wellbeing.

Headache Australia is proud to be at the forefront of this world first initiative to help headache sufferers. The summit did help participants feel that they were not alone and work is being done constantly to understand and find treatments to reduce the terrible impact that this condition has on their lives.

Together with the help of Headache Australia’s register members, the World Summit has raised thousands of dollars for migraine research. To find out more and for access to the talks, please visit migraineworldsummit.com

ANZAN 2017 shines a light on headache

Botox® will put a smile on your face!

This years’ Scientific Meeting for neurologists focused on the area of headache. Experts from the UK, USA and Europe came together with colleagues from Australia and New Zealand and offered expert insights and knowledge into this area of speciality.

It has now been a few years since Botox® was approved for the PBS in Australia for chronic migraine sufferers (15 or more headache days per month with 8 days being migraine) and many people have reported giving it a go. Like all migraine treatments, it does not help everyone. But, it was reported at the recent ANZAN conference that Botox® has helped reduce or even almost eliminate migraines for 75% of people who have tried it.

It is good to see that headache and migraine is being recognised as the disability that it is and attracting more attention worldwide. More shared knowledge means better diagnoses for patients. There are new treatments on the horizon to offer hope for better outcomes for sufferers.

Worth a go? Ask your doctor or look up chronicmigrainehelp.com.au for a practitioner in your area.

Cefaly – the buzz continues you buy, we also have a lend programme. You will receive a Cefaly device for 6 weeks to trial. Just ring our office to be placed on the waiting list. For more information about Cefaly see cefaly.com.au Cefaly’s popularity continues to grow with patients and doctors alike. 75% of people who have used the TENS machine, report at least a 50% reduction in their headaches. Cefaly works particularly well for those with headaches at the front and side of the head. You can purchase a Cefaly device from Headache Australia. Or, if you would like to try before

Cefaly Winner Last year Headache Australia asked members to relate their journeys with migraine for the chance to win a Cefaly device. Our winner was Ellie Freeman, a university student – now in full time employment – from Sydney. She wrote: I was extremely grateful to Headache Australia for awarding me this device. The CEFALY

has been a huge help towards improving my quality of life & lessening my migraine attacks. I suffer from chronic migraine & even on days where I don't have a migraine, I wake up with the constant headache feeling - like a dull ache that feels like you're getting a migraine & all other symptoms that come with an attack. Now that I have the CEFALY device it is a relief; using it daily as a preventative seems to reduce the amount of migraines I get but also the severity of them. It hasn't stopped them completely but sometimes when I feel the migraine coming on if I use the CEFALY straight away my migraine goes away.

Are you a Headache Register Member? Our Register Members receive regular email updates of current information as we receive it. We send information about new research trials that you can choose to be involved with. All donations made by Register Members go only to Headache research. Your email address is required. Register at headacheaustralia.org.au

At times where I really struggle with severe attacks the CEFALY still provides me with a little pain relief & it can be relaxing at times as well... it feels like a massage for your brain.

Headache Awareness Week 2017 September 11 to 16 Look out for emails outlining online events for our Register members.

Disclaimer: Headache Australia is not a medical office and cannot offer medical advice. We stress the importance of discussing any issues you have with your medical practitioner.

Winter 2017


2017 Progress Reports Major Research Gift 2015

A new understanding of increased pressure within the skull in brain diseases

Chief Investigator: Dr Neil Spratt Stroke is a leading cause of death and disability in Australia, with over 1000 Australians impacted by this disease every week. By the end of 2017 more than 470,000 Australians will be living with the effects of stroke. The cost of this ongoing disability to the government, taxpayers and individuals is estimated to be $5 billion per annum. However, the biggest impact of stroke is not financial, but the loss of healthy life, with over 65% of survivors suffering disability impeding their daily living activities. Currently, effective treatment options are limited and government investment into stroke research is relatively low. Improved treatments require better understanding of the cause and effects of stroke. One effect that has long been observed is an increase in pressure due to brain swelling following a large stroke. When the brain is injured, much like any other part of the body, swelling occurs. However the skull constricts the swelling

brain, causing an increase of pressure on the brain (known as intracranial pressure). This swelling can prevent adequate blood flow to the brain, with even very small changes in brain volume having a crucial impact on the patient’s outcome following a stroke. Prof Neil Spratt’s team has recently discovered that even small strokes may lead to an intracranial pressure (ICP) rise, without noticeable brain swelling. This novel finding demonstrates that it is not the brain swelling that causes increased ICP in minor stroke. Excitingly, we recently showed a significant ICP rise in stroke patients 24 hours after onset of their stroke, using a new non-invasive method developed by our collaborator Dr Bernhard Schmidt, from Chemnitz, Germany. These results were presented at the very recent European Stroke Conference in Prague. Our data points to an increased volume of cerebrospinal fluid (CSF) surrounding the brain. Studies of changes in CSF production over time have shown that assaults to the brain (such as minor stroke) may disrupt the water channels (called Aquaporins) in the brain, which serve to regulate the CSF volume. With the help of funding from the Brain Foundation, Prof Spratt’s team have explored the reasons for this channel

disruption. By comparing samples of CSF from patients who had suffered ICP elevation with control samples of healthy people, differences in protein expression were mapped. Ongoing analysis into the types of proteins that are changed, and their action on the body’s pathways, will allow identification of the key molecules responsible for the ICP increases. Better understanding of this process will allow researchers to develop optimised treatments for ICP rises. Current treatments to prevent ICP increases following minor stroke are limited to diuretic drugs and surgical intervention. An exciting finding of Prof Spratt’s research has shown that the pressure rise can be completely prevented by a short duration of body cooling. This non-invasive treatment has the potential to reduce disability post-stroke, as well as prevent further secondary strokes. Further research is underway to determine the safest and simplest methods of skin cooling in healthy volunteers. This work will be expanded into a clinical trial involving patients with neurological deterioration, and has the potential to greatly improve the recovery of future stroke victims by restoring mobility and functionality of speech, cognition and limbs, and wellbeing for themselves and their families.

Additional research is exploring how a stroke can generate long-term changes in cerebrospinal fluid movement. When we sleep there is an increased movement of fluid through the brain, which is believed to “flush” out potentially harmful excess proteins and waste products (the presence of which has been linked to dementia). Research has shown an increased prevalence of dementia in stroke patients. In collaboration with A/Prof Rohan Walker also from the University of Newcastle, Prof Spratt’s team has discovered a reduction in fluid flow and accumulation of detrimental proteins in the brain up to two weeks after stroke. This important finding may shed light on why stroke patients are at greater risk of losing mental function or developing dementia, even many months after their stroke. Further research in this area will determine how ICP rises and altered fluid flow are associated, and how this may cause delayed cognitive decline following a stroke. This research would not have been possible without the support of the Brain Foundation. With this support we hope to bring all the pieces together and determine the contribution of ICP elevation to stroke outcome, and develop improved treatments to benefit the many patients who suffer from a stroke.

Substance P: Targeting brain swelling to improve long-term outcome following stroke Chief Investigator: A/Prof Renee Turner

Cerebral oedema and the subsequent development of raised pressure within the brain are life-threatening complications of stroke associated with a significant burdenof mortality and poor outcome in survivors. Despite this, treatments remain limited and fail to address the cause of

2014 Brain Foundation Grant

the swelling. As such, new treatments are urgently required.

stroke and thereby improve outcome long-term.

We have discovered that the neuropeptide substance P is involved in breakdown of the blood-brain barrier and subsequent development of cerebral oedema and poor outcome following stroke. The purpose of this study was to assess whether blocking the action of substance P by administering an NK1 antagonist would reduce the development of cerebral oedema and in turn improve outcome.

Indeed, this is exactly what we have found. To date, we have shown that treatment with the NK1 antagonist improves outcome, as measured at 7 days following stroke. Specifically, treatment with the NK1 antagonist has reduced the level of disability observed following stroke.

Hypothesis vs Findings We hypothesised that by blocking the action of substance P, we could reduce cerebral oedema formation following

Unanswered Questions Studies are still ongoing and we are in the process of assessing whether this improvement in outcome we have observed is sustained beyond 7 days following stroke.

What these research outcomes mean Our findings suggest that treatment early on following a stroke with an NK1 antagonist may be beneficial in reducing the development of cerebral oedema and in turn improving both outcome and survival. Essentially, if we can reduced the development of cerebral oedema and its associated deleterious consequences then we may be able to save patients lives and improve their long-term outcome. Clinical assessment of the NK1 antagonist is currently underway, with Phase I clinical trials being conducted by CMAX to assess the safety of the compound and the next step to test the intervention in patients who have suffered injuries to the brain.

See website for complete reports and References 4

The Newsletter of the Brain Foundation

Can expression of the NFI pathway be used to treat primary human GBM? Chief Investigator: Dr Jens Bunt 2014 Brain Foundation Grant

patients. In cultured GBM cells, re-introduction of NFI stops cancer cell division and promotes the transition of these cells into glial cells, as such effectively reversing the cancer. Therefore, we propose that activating NFI expression will provide a novel complementary strategy for clinical treatment of GBM. In this project, we are testing the hypothesis that activating NFI in primary human GBM tumours will stop their growth and reverses the cancer. Therefore, we have established a new pre-clinical model. We are now growing human primary GBM tumours in mice on which we can do clinical testing. In short, we obtain primary human tumours directly from the operating theatres of Brisbane hospitals via the Wesley Medical Research Tissue Bank. These tumours are than injected and maintained in mice as so-called xenografts. Currently we have different xenografted tumours available for experiments and are generating more to create a xenograft bank for researchers. Hypothesis vs Findings

Glioblastoma (GBM) is a devastating primary brain cancer that affects around 800 Australians annually. Despite surgery, radiotherapy and chemotherapy, 1 in 2 patients diagnosed with GBM will not survive for more than 14 months and fewerthan 1 in 10 patients will survive for five years. This short life expectancy highlights the need for novel and effective therapies for the treatment and cure of this deadly disease. We are developing a potential new therapeutic strategy, focussing on the glial origin of GBM, to complement the current treatment following tumour resection.

Using immunofluorescence analysis, we have determined that in human tumours NFIB is mainly expressed in the tumour cells that are not proliferating, and more proliferative tumours have less NFIB expressing cells. To increase expression of NFIB in the dividing tumour cells, we have optimized a technique called in vivo electroporation, in which NFIB-expressing or control DNA constructs are injected into the tumour and a small electric current is applied over the tumour. This current pulls the DNA construct into the tumour cells. In the case of the NFIBexpressing construct, this will lead to expression of NFIB in these cells. As the DNA constructs also express a fluorescent marker, we can readily identify which cells are treated with NFIB (See figure).

Glial cells are essential for normal brain development and function, as they play important roles in regulating synapse formation and function as well as supplying nutrients to neurons. GBM tumours originate from this cell type. If we can reactivate the glial differentiation programme that normally drives the production of glial cells in the brain, we can potentially induce the differentiation of cancer cells and prevent further tumour growth, independent of the underlying molecular events driving disease progression. Nuclear Factor One (NFI) is a family of genes required for normal glial biology transcription. Transcription factors are master regulators of gene expression, thereby coordinating the expression of other genes during developmental processes such as proliferation and differentiation. In GBM, these genes are often deleted or mutated. As NFI genes drive the differentiation of glial cells during brain development, they may act as tumour suppressors in GBM. NFI expression directly correlates with clinical outcome (less NFI = shorter patient survival) and for the gene NFIB, decreased gene copy number is associated with adverse disease progression and clinical outcome for

for two patients. Based on immunohistochemical staining and flow cytometry data, we confirmed that NFIB-treated cells within the tumour show less proliferation and less tumour characteristics. Although we need to further analyse the treatment on tumours from other patients, our data unequivocally proves that activation of NFIB in established tumours can stop tumour growth. Unanswered Questions Recently published findings from our group showed that not all human tumours respond similar to NFIB treatment. While the tumours from the most aggressive subtypes displayed growth reduction when implanted in mice, some less aggressive tumours did not respond to NFIB treatment, and some even grew faster. Therefore, we need to understand why some tumours do not respond to NFIB treatment and find a way to diagnose the patients who will benefit from this treatment. Therefore, we are expanding our research using the now established xenografts and electroporation method to understand the molecular mechanism that determines whether NFIB treatment results in reduced or increased tumour growth. With the data generated using the Brain Foundation gift, I have been able to obtain a Scott Canner Young Researcher Grant from Tour de Cure to fund this line of research. Furthermore, together with researchers within the Australian Institute for Bioengineering and Nanotechnology and the Centre for Advanced Imaging at the University of Queensland, we have now started to investigate how NFIB can be administered and how to monitor its effect on tumour growth. We are testing the use of nanoparticles as an targeted drug-delivery method. Finally, we are imaging the progression of tumours when the level of NFIB is altered to verify its effectiveness. What these research outcomes mean Given the poor outcome and low quality of life of surviving patients with GBM, alternative and radical approaches are required to target this devastating desease.

An overview of the electroporation technique to introduce NFIB expression in human tumour xenografts. Human tumours are grow as xenografts under the skin of mice. To induce NFIB, an expression construct is injected into the tumour. Subsequently, this DNA construct is pulled into the tumour cells by an electric current. The tumours cells will now expressed NFIB (depicted in red) as well as a green fluorescent marker (GFP; in green) to easily identify treated cells

We are now able to manipulate NFIB in established tumours that closely mimic the GBM tumours in human patients. We already tested NFIB treatment in xenografted tumours

Current research has focused mainly on targets involved in driving tumour cell proliferation, which may differ between subtypes of GBM. In our approach we regard GBM as a disruption in the normal development of glia in the brain. NFI plays an important role during normal brain development, as it induces the transition from proliferation to glial differentiation. Based on our current results, we can conclude NFIB activation is able to act as a tumour suppressor as it stops proliferation of tumour cells of human tumours. Although we need to further investigate how to identify patients that will respond to this treatment and how to deliver NFIB to the tumour cells in human patients, our research has provided the critical proof-ofprinciple that NFIB or other glia differentiation genes can be developed into successful clinical therapeutic agents.

Did you know? Brain tumours/cancer kills more children than any other disease

Brain tumours/cancer kills more people under 40 than any other cancer

Survival rates for brain tumours/cancer have not improved in 30 years

We need your support to improve these statistics.

Winter 2017


2017 Progress Reports Activity dependent regulation of Parkinson’s disease associated synuclein in presynaptic plasticity Chief Investigator: Dr Mark Graham

A hallmark feature of the pathology Parkinson’s Disease and related neurodegenerative disorders is the presence of Lewy bodies in neurons. Alpha(α)-synuclein is the predominant component of Lewy bodies, which are made of aggregated proteins. The normal biological function of α-synuclein in neurons is not well understood and this limits the understanding of how α-synuclein contributes to disease. Like most proteins, the function of α-synuclein is regulated by phosphorylation, which is a chemical modification of protein side chains. Phosphorylation is a signalling mechanism within cells that changes the function of proteins in response to environmental stimuli. An example of changed function is when phosphorylation prevents two proteins from interacting, which might stop a particular biological process. The α-synuclein in a healthy brain has very low levels of phosphorylation and is difficult to detect. The α-synuclein in Lewy bodies is highly phosphorylated and so phospho-signalling is relevant

to the disease state. We have studied the phosphorylation of α-synuclein in neurons in response to the signals associated with neurotransmission. We discovered a new phosphorylation on α-synuclein. The phosphorylation site is interesting because it is in the part of α-synuclein that likely binds to synaptic vesicles. Synaptic vesicles are the tiny packets of neurotransmitter that fuse with the neuronal membrane to allow neurotransmission. Our aim was to develop tools to study the role of the new phosphorylation site and to determine how phospho-signalling changes α-synuclein function.

a large number of proteins; however, the methods used don’t indicate the dynamic binding that might occur during neurotransmission. We compared the proteins that bind to α-synuclein, before and after a stimulus that normally evokes neurotransmission. Six hundred and twenty three interacting proteins were identified. A small subset of proteins changed their binding to α-synuclein following a stimulus, indicating more clearly that they are involved in the same biological process as α-synuclein. We are now continuing our investigation of these candidates to shed light on normal α-synuclein function.

The main tool developed was an antibody for the new phosphorylation site on α-synuclein. The antibody was confirmed as being specific for only the phosphorylated α-synuclein. In a continuation of this project, this validated tool is now being used to answer a number of questions about how the phosphorylation affects α-synuclein function. In parallel, we investigated how signalling that occurs during neurotransmission affects which proteins bind to α-synuclein. Previous research has shown that α-synuclein can bind

Hypothesis vs Findings

Brain Awareness Week 2017

We hypothesised that the α-synuclein phosphorylation site we discovered was involved in regulating neurotransmitter release and/or synaptic plasticity. We found that several proteins changed their interaction with α-synucleinfollowing a stimulation that evokes neurotransmitter release. Also, we have generated many tools to further test this hypothesis, including the first phospho-specific antibody to this site, phospho-mimetic and phospho-deficient mutant plasmids

Our flags flew in Sydney city for the week and added a touch of colour to our streets.

DYSTONIA Support Group Dystonia is the third most common movement disorder worldwide. The cause, while neurological in origin, is unknown. ADSG Website: australiandystoniasupportgroup.wordpress.com/ ADSG Community Page: facebook.com/AustralianDystoniaSupportGroup ADSG Closed Support Group on Facebook: facebook.com/groups AustralianDystoniaSupportGroup/

The Newsletter of the Brain Foundation

for this site to be used in both in vitro binding experiment and cellular assays to directly test the effect of phosphorylation on neurotransmitter release. These experiment are currently being done by a new collaboration arising from this work. Unanswered Questions As stated above, the bulk of the project involved tool generation and so these tools are only now being used to properly test the hypothesis. Furthermore, the findings indicate that there are likely a small number of proteins which change their binding characteristics towards α-synuclein following a stimulus. We can now determine the nature of these interactions. What these research outcomes mean For the first time there is an antibody and a suite of molecular genetics tools for a particular novel phosphorylation site that can be used to advance α-synuclein and Parkinson’s Disease research. As a result of this project, a major collaboration has been initiated to advance knowledge in this area. The tools and data generated are now being used to leverage further funding, answer bigger questions and enable more collaborations.

Tamworth Christmas Fair

This year, Brain Foundation encouraged our supporters to take up the challenge of a Trivia evening. We supply the whole kit to organisers and participants pay a donation to be part of the fun. This proved to be very successful and we are hoping for an even bigger 2018.


2014 Brain Foundation Grant

This wonderful, annual event will be taking place at the Tamworth Racecourse on Sunday November 19. If you are in the area or just travelling by, drop in and take a look at all the interesting market stalls. You could get all your Christmas shopping done nice and early!

The ability of progranulin to acutely decrease blood brain barrier permeability, attenuate brain injury and reduce functional impairment following experimental stroke Chief Investigator: Dr Katherine Jackman

2014 Brain Foundation Grant

Fig. 1. Treatment with progranulin (100, 200 ng) upon induction of reperfusion failed to exert neuroprotection against ischaemic stroke.

The goal of this project was be to evaluate the therapeutic attributes of progranulin for the acute treatment of ischaemic stroke by exploring the influence of treatment with progranulinon blood vessel leakiness and the impact of stroke. The first aim was to evaluate the abilityof treatment with progranulin (recombinant protein, injected intravenously) to reduce ischemic brain injury in response to ischemic stroke. Stroke was induced in C57Bl/6J mice using the technique of intraluminal middle cerebral artery occlusion (MCAO) and mice were treated with either Vehicle or progranulin (100, 200ng) at reperfusion (0hrs). As shown in Figure 1, we did not observe a protective effect of progranulin, as infarct volume, oedema and behavioural function. Deficits were similar in all three groups (Fig.1).

Given this negative finding we decided to redirect the focus of the study on the effects of progranulin on blood brain barrier (BBB) integrity. In collaboration with Robert Medcalf, we characterized the ability of progranulin to stabilize vascular integrity using an in vitro BBB model1. We demonstrated that progranulin can rapidly promote BBB integrity in response to combined permeability insults including oxygen glucose deprivation (Fig. 2A) and combined tissue plasminogen activator (Fig. 2B). These and other complementary findings support the therapeutic benefit of using progranulin to increase BBB integrity in response to injury. By adding progranulin selectively to the luminal (endothelial) or abluminal (astrocyte) side of the transwell system, we demonstrated that both endothelial cells and astrocytes contribute to the vascular stabilizing effects (Fig. 2A). We have shown that progranulin prevents changes in endothelial cell morphology that occur in response to permeability insults (data not shown). In addition, we have confirmed that the recently described progranulin binding partner sortilin does not mediate these effects (data not shown).

Collectively, these findings do not support the usefulness of progranulin as a treatment for acute stroke. However, they do support beneficial effects of progranulin on blood brain barrier integrity. While progranulin may not be able to offset the massive degree of BBB disruption that occurs in stroke, it may be valuatble in diseases in which the degree of BBB disruption is more modest and sustained (e.g. multiple sclerosis). These findings are currently being prepared for publication and will be submitted this year.

Fig. 2. Investigating the BBB stabilizing effects of progranulin using an in vitro system. A. Progranulin (400 ng) attenuates BBB permeability in response to oxygen glucose deprivation. Interestingly, progranulin stabilizes the BBB when administered to either the luminal (endothelial) or abluminal (astrocyte) side of the transwell, suggesting that both cell types contribute to vascular stability (n=8, *P<0.05, ANOVA). B. Progranulin attenuates BBB permeability in response to combined oxygen glucose deprivation and tissue plasminogen activator(tPA, n=7, *P<0.05 versus control, Ψ versus OGD tPA, ANOVA).

Exercise your brain Healthy Brain Exercise your most important asset. It is irreplaceable! It is you! Thanks to Super Trivia guy.

Cryptogram Quotes Solve the number/letter code to reveal the cryptogram quote, and the person who said it. Keep in mind, not all the letters of the alphabet are used in the cyptogram.

Winter 2017


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In Memorium

Supporting brain research is superannuation for your brain!

The Brain Foundation would like to extend a very sincere thank you to the families of the following who supported us in a time of great sadness and loss.

With most brain diseases and disorders having no treatment that is able to reverse the devastating effects, it is now more important than ever to support brain research. New treatments take years

to come to the market after the initial discovery. Wouldn’t you like to know that, should you need it, a treatment is available. Support brain research today for better treatment options tomorrow.


Headache Facts Migraine is the third most prevalent disorder worldwide

Warren SOLLY Lorna Gwen JACKSON Less than 50% of sufferers consult a physician. It remains underdiagnosed and under treated.

Kevin CONNELLY Professional diagnosis provides best treatment options.

Roslyn TREW Barrymore Douglas NICOL Jill HUNTER Renzo TOMASINO Peter DUNCAN Graham John COXON

Like to help? Fundraising is easy People who fundraise for us usually do so because they have a cause close to their hearts. Fundraising is not so hard. Visit one of the online fundraising sites for inspiration or to join a public event, such as one of the many fun runs. gofundraise.com.au, mycause.com.au, everydayhero.com.au

Thanks go to the following: My Cause: Callum Smith – Port Phillip Paddle, Melbourne, Brisbane and Perth Zombies, all our wonderful Big Trivia organisers and players. Go Fundraise: Cheryl Doyle – Cocktail Party Fundraiser, Hayden Delos – shaved his head for Brain Tumours, Laura Chapple and friends who walked the Camino track. Everyday Hero: Chelsea Keynes who ran the Bridge to Brisbane and Monique Waymouth who swam to Rottnest Island

Coral Elizabeth SISSON Kay WILLIAMS Helen Megan HOLLIS

Bequests We gratefully acknowledge the following for their very generous contributions to our Research Programme. Betty Ilic Thelma Joyce Jeffrey Catherine Gilbert Brown

Regular Giving

Dawn Wallace

Would making small, regular donations suit you better than one bigger donation per year? Perhaps you should think about making a regular monthly or quarterly donation. Contact our office or download a form and we will do the rest for you.

Workplace Giving is an easy alternative and your company may even match your donation. Speak to your paymaster for further information. for Brain Foundation supporters. For more information, please call Gerald in our office on 1300 886 660.

Thanks to the following companies for their support:

Thank you for supporting brain research through the Brain Foundation To make a donation please visit our website brainfoundation.org.au/donate or use the donation form on the letter enclosed.

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Estate Planning and Bequests: Our benefactor, Australian Executor Trustees offers reduced rates