The Research We Fund

Charting new neuronal survival pathways in Parkinson's disease

Parkinson’s disease is an incurable brain disease where dopaminergic neurons die, but interestingly, cortical neurons initially resist death. Two major contributors of dopaminergic neuronal death are toxic protein aggregation and impaired metal balance. Loss of a metal transporter, ATP13A2, in dopaminergic neurons causes abnormal protein aggregation resulting in neuronal death. However, loss of ATP13A2 in cortical neurons shows similar protein accumulation, but the cells survive. Dr Indranil Basak's project hypothesises that cortical neurons possess protective mechanisms to tackle toxic protein accumulation and metal imbalance. Investigating these protective mechanisms in cortical neurons will identify novel targets that could treat vulnerable dopaminergic neurons.

Genetic causes of syndromic neurodevelopmental disorders in New Zealand families

Studying the genetic causes of neurological disorders has tremendous power to connect disrupted genes with altered brain development. Dr Louise Bicknell proposes to study individuals impaired by disrupted neurodevelopment, using the latest DNA sequencing technology to pinpoint possible disease genes. She will utilise both patient cells and a new neural stem cell resource to generate evidence confirming disruption of these genes alters cell functioning and underlies disease, while also gaining insight into these genes in brain development. The overarching goal for this project is to directly help families affected by neurodevelopmental disorders using both genetics and molecular biology research.

Identifying superheroes in neurodegenerative disease

Brain diseases, such as Alzheimer’s and Parkinson’s disease, are uncurable. The recently described “superhero gene” concept provides a new way to understand and treat these diseases. Superheroes are individuals who have the genetic mutations that would usually guarantee severe disease, but never develop the disease because a variant in a second “superhero gene” compensates in some way. Identifying superheroes on a population-wide basis requires sequencing of millions of individuals. Instead, Associate Professor Stephanie Hughes will screen for superhero genes in a novel human neuronal model. This work has the potential to generate new targets for therapies for a range of brain diseases.

Role of ryanodine receptors in Alzheimer’s disease

Part of a larger study funded by the Health Research Council of New Zealand

Alzheimer’s disease (AD) is a major concern for New Zealand’s aging population. Treatment is limited due to inadequate knowledge of the cellular changes occurring during AD. Studies show that inappropriate leak of calcium, through a protein (RyR2), can cause AD. However, why this leak occurs is poorly understood. Within the heart, we have shown that calcium leak is caused by the inappropriate arrangement of RyR2 within the cell. This project will determine if a similar mechanism underlies calcium leak in AD. It will also examine whether drugs known to prevent calcium leaks in the heart also work in the brain.

Validation of the Time to Walking Independently after Stroke Tool (TWIST)

Around 10,000 New Zealanders experience stroke each year, and most will have difficulty walking afterwards. Regaining the ability to walk independently can make the difference between returning home or having to move to a rest or nursing home. Patients and whānau/family would like to know whether they will walk independently again and how long this will take. Unfortunately, clinicians' predictions are accurate only about half the time. The TWIST tool predicts both whether and when a patient will walk safely on their own again, with 90% accuracy. This study will validate TWIST so it can be implemented in clinical care.

Use of a novel gene switch to refine the application of gene therapy for Huntington's disease

Co-funded with the Auckland Medical Research Foundation (AMRF)

Gene therapy is beginning to deliver impressive therapeutic benefits for some diseases in humans including those affecting the brain. Associate Professor Deborah Young has developed a novel gene switch for use in gene therapy that harnesses disease-specific signals to switch on and restrict the production of the therapy to sick neurons only at the time of need. This project will test the functionality of the gene switch in driving a therapy to ameliorate the development of neuropathological and behavioural deficits in a preclinical model of Huntington's disease. This research will help facilitate the advancement of gene therapy from the bench to the clinic.

Decoding the regulatory activity of disease associated SNPs within the Parkinson’s network using a Massively Parallel Reporter Assay (MPRA)

Parkinson’s disease is a complex neurodegenerative disorder that affects more than 6.2 million individuals worldwide. 200 genetic mutations have been linked to Parkinson’s disease. However, clinicians and scientists have a limited understanding of how these mutations affect disease development and progression. Miss Sophie Farrow thinks these mutations work together as a network. She will use computational and laboratory techniques to decode this network and how these mutations interact and work together. These findings will help her team determine new ways to treat Parkinson’s disease as well as providing options for personalising the current treatments available.

Identification of adhesion molecules metastatic melanoma uses to invade across the brain endothelium

Brain metastases are present in the majority of individuals who develop advanced melanoma. They are particularly challenging to treat and associate with worsened clinical outcomes. During the metastatic process, the tumour mass sheds cells into the blood. It is from the blood that these metastatic cells gain entry into the brain and other tissues. Therefore, our goal is to identify how these metastatic cells cross the brain endothelial barrier and gain entry. If this project can identify the molecules involved, it will provide targets to reduce or suppress this devastating process.

Targeting the inflammasome pathway in neuroinflammatory diseases

Two pathologies, inflammaging (cumulative immune system deficiency) and telomere shortening, play central roles in the pathogenesis of neuroinflammatory diseases. Dr Lola Mugisho has previously shown that the inflammasome is a disease pathway that regulates inflammaging in neuroinflammatory diseases. However, it remains unknown whether this pathway also regulates telomere attrition. Using cell culture and mouse aging models, Dr Mugisho aims to determine whether inhibiting inflammasome activation will prevent telomere shortening thereby decreasing the risk of developing neuroinflammatory diseases. This study will further the understanding of the aging process and enable future studies that explore targeting  the inflammasome pathway to treat age-related neuroinflammatory conditions.

Identifying spatiotemporal microglial activation changes in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a paralysing brain and spinal cord disease caused by the death of neurons involved in movement. Brain immune cells called microglia, which normally help the brain recover from damage in disease, are also affected in ALS. Microglia appear to become ‘toxic’ late in disease, promoting the death of neurons and worsening the disease. Microglial changes will be investigated in the brain tissue of people who have died of ALS and in different disease stages of an ALS animal model. This research will contribute to understanding how microglia contribute to ALS at different stages of disease.

The use of novel biomarkers to predict the development and severity of chemotherapy- induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) occurs when nerves in the arms and legs are damaged by drugs used to treat cancer. CIPN occurs in 30- 40% of people treated with some cancer drugs, but it is unpredictable and can sometimes be severe and disabling. Neurofilament light chain (NfL) is a protein, measurable in blood (a biomarker), which has been found to be elevated in other causes of damage to peripheral nerves. This study will measure levels of NfL and two other biomarkers in patients receiving chemotherapy to determine whether they can be used to predict the development and severity of CIPN.

Management of Systolic blood pressure during Thrombectomy by Endovascular Route for acute ischaemic STROKE: the MASTERSTROKE trial

Stroke is the third most common cause of death worldwide and is the leading causes of long-term disability at all ages. A life-saving clot retrieval procedure can save lives if the clot is removed early enough. In New Zealand, these procedures are performed under general anaesthesia and blood pressure (BP) management during the procedure is critical. A higher BP might improve blood supply around the stroke, but high BP could increase bleeding. A large trial is the only way to test the appropriate BP management during clot retrieval and further improve outcomes for stroke patients in New Zealand having this remarkable new treatment.