Neurogenetic diseases


Student project opportunities



Disease gene discovery for (neuro)genetic diseases

Research area: Molecular genetics, neurogenetics, molecular biology, bioinformatics
Chief supervisor: Professor Nigel Laing
Other supervisors: Associate Professor Kristen Nowak, Dr Gina Ravenscroft
Project suitable for: Honours, Masters, PhD  
Essential qualifications: BSc
Start date: Flexible

Project outline
Determining the genetic cause of a disease is vital information for patients and their families, their clinicians, and the medical researchers studying that disease. Once the genetic defect is known, some of the direct outcomes are that:

  • A molecular genetic diagnosis can be given to the patient, and genetic counselling can be better informed (e.g. disease prognosis, determining the likelihood of further family members being affected by the disease)
  • Medical researchers can better study the pathobiology of disease (e.g. how does the defective or missing gene actually cause the disease?)
  • Medical researchers can rationally design potential therapies and evaluate their efficacy

The Neurogenetic Diseases Laboratory has identified >25 new disease genes, for a range of diseases, though mainly neurogenetic diseases. It is currently a very exciting era in molecular genetics due to the availability of “next generation sequencing” tools. Researchers now have the capacity to “crack” the disease genes for many more patients and families than they were previously able to. We can also investigate genetic modifiers of disease, such as why some people in the same family have a milder disease than others. If we could learn why this happened, we could tap into the cause as a potential therapeutic route.

The Neurogenetic Diseases Laboratory is a leading laboratory, in Australia and internationally, in the application of next generation sequencing techniques for neurogenetic diseases. There has been a rapid increase in the number of new disease genes being identified. Through the Laboratory's local, national and international collaborations (both clinical and scientific), this research Laboratory always has interesting families and groups of patients available for study. If you’d like to be at the cutting edge of the disease gene discovery field, making an immediate, significant and direct impact on the patients you study, please get in touch to discuss the Laboratory's latest projects in disease gene discovery.

Contact
Professor Nigel Laing - Nigel.Laing@perkins.uwa.edu.au

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Pathobiology of genetic diseases

Research area: Recombinant protein production, tissue culture, molecular biology, animal models, physiology
Chief supervisor: Professor Nigel Laing
Other supervisors: Associate Professor Kristen Nowak, Dr Gina Ravenscroft, Dr Rhonda Taylor
Project suitable for: Honours, Masters, PhD  
Essential qualifications: BSc
Start date: Flexible

Project outline
Having a good insight into the pathobiology of a disease is necessary not only for a better understanding of what is occurring in the diseased tissues of patients, but also for deciphering what normally happens in non-diseased tissues. Thus medical researchers strive to unravel how the defective protein produced from the disease gene, or indeed a missing gene product, actually causes disease.

The information gained from pathobiological studies is often the clincher in proving that a variant in a particular gene is disease causing. Therefore significant headway in the area of pathobiology usually occurs in conjunction with the discovery of new disease genes, or when previously known disease genes are identified as causing a different phenotype. Knowledge of the pathobiology of a disease is essential to rational design of potential therapies for patients. Due to the strong gene discovery arm of the Neurogenetics Disease Laboratory, there is a suite of different pathobiological studies occurring within this lab. These studies are focussed predominantly, but not exclusively, towards neurogenetic diseases. The techniques involved include tissue culture experimentation, production and purification of recombinant proteins, protein modelling and analyses of mouse models. Studies are often conducted in collaboration with a range of strong collaborators from around the world.

If you’d like to be involved with proving that a putative disease gene is indeed the one at fault for a given disease, and/or resolving the processes which underpin a defective gene leading to a diseased tissue, please get in touch to discuss the latest projects being offered by this research Laboratory.


Contact
Nigel Laing - Nigel.Laing@perkins.uwa.edu.au

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Devising and evaluating therapies for neurogenetic diseases

Research area: Mouse models, adeno-associated viral delivery, CRISPR technology, tissue culture, genetic engineering, mouse phenotyping
Chief supervisor: Professor Nigel Laing
Other supervisors: Associate Professor Kristen Nowak, Dr Gina RavenscroftDr Rhonda Taylor
Project suitable for: Honours, Masters, PhD  
Essential qualifications: BSc
Start date: Flexible

Project outline
Having the ability to study animal models is often crucial for medical researchers to devise and then evaluate potential therapies for disease. Even if certain experiments can be performed in tissue culture, ultimately studies require an animal model to be the test-bed to allow appropriate and thorough evaluation. This research laboratory has extensively studied a range of neurogenetic diseases in mouse models, and is continuing to do so. Techniques used to phenotype mice include tissue biopsy and histology, immunostaining, various types of microscopy, protein and RNA extraction, voluntary running wheel analysis, muscle physiology, and magnetic resonance imaging.

Knowledge of the disease gene, and often pathobiology too, is used to rationally design potential therapies for patients, e.g. a drug might be used to circumvent what is going wrong, or a virus could deliver the missing protein and prevent/reverse disease. We have additionally trialled a range of therapeutic approaches with the mouse models we have characterised. These include successful work upregulating an alternative gene from the same gene family as the one that is causing the disease. Various other approaches such as viral delivery, and CRISPR technology are currently being evaluated.

Successful proof of concept experiments in a mouse model, are significant steps in the right direction towards disease prevention or a cure. However once they have been conducted in a mouse model, such experiments need to be translated to a human setting if they are not already applicable to one.

Please contact us to discuss the possible projects on offer in the Neurogenetic Diseases Laboratory therapies team if you are inspired to try to develop therapies for diseases. If you choose such a project, you would use a range of exciting techniques in a well-established and respected laboratory, and in many cases in collaboration with first-rate international collaborators.

Contact
Associate Professor Kristen Nowak - kristen.nowak@perkins.uwa.edu.au

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Identifying the genetics and pathobiology of neuromuscular diseases presenting before or at birth

Research area: Molecular Medicine and Aging
Chief supervisor: Professor Nigel Laing
Other supervisors: Dr Gina Ravenscroft
Project suitable for: Honours, Masters, PhD  
Essential qualifications: relevant undergraduate science degree or medical degree
Start date: Flexible

Project outline
Neuromuscular diseases are frequently genetic and debilitating. At the most severe end of the spectrum are cases, which present prior to birth (in utero) or at birth. Neuromuscular diseases with onset prior to birth can result in a number of clinical presentations including: reduced or absent foetal movement, reduced muscle bulk and arthrogryposis (multiple joint contractures). At birth, patients with severe neuromuscular disease present with poor muscle tone and weakness, respiratory insufficiency. Most cases do not survive the neonatal period. Over the past five years, the Neurogenetics Laboratory in collaboration with local, national and international colleagues have amassed a unique cohort of patients (>220 cases from over 180 unrelated families) presenting with a neuromuscular disease prior to birth. To date, we have been involved in the identification of five novel disease genes for this group of patients; and these findings have facilitated prenatal diagnosis of subsequent pregnancies for affected families. Despite these successes, there are many more disease genes to identify in this patient cohort and many more families without a genetic diagnosis.

This project combines cutting-edge next generation sequencing, linkage studies and traditional Sanger sequencing to unlock the genetics of these diseases. In addition, histology, immunohistochemistry, western blotting and cell culture studies will be used to validate candidate disease genes and variants and to prove pathogenicity.

Suggested Reading

  1. Ravenscroft G, et al. (2011) Foetal akineisa – review of the genetics of the neuromuscular causes. J Med Genet 48:793-801.
  2. Ravenscroft G, et al. (2013) Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy. Am J Hum Genet 93(1):6-18.
  3. Ravenscroft G, et al. (2013) Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations. Neuromuscul Disord 23:165-169.


Contact
Professor Nigel Laing - Nigel.Laing@perkins.uwa.edu.au
Gina Ravenscroft - gina.ravenscroft@perkins.uwa.edu.au

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Non-UBA domain SQSTM1/p62 mutations in Frontotemporal dementia and motor neurone disease

Research area: Genomics, Genetic Disease, Cell Biology
Chief supervisor: Dr Sarah Rea
Other supervisors: Professor Nigel Laing
Project suitable for: Honours, Masters, PhD
Essential qualifications: BSc
Start date: Flexible

Project outline

Frontotemporal dementia and amyotrophic lateral sclerosis are the most common forms of early onset dementia and the most common motor neuron disease, respectively. They exist on a disease spectrum, with ~15% of patients having both FTD and ALS. Although many common genes have been associated with disease risk, approximately 90% of cases are not heritable. Importantly, the two diseases are characterized by aggregation of Tar DNA binding protein 43 (TDP-43, encoded by TARDBP) within neuronal cytoplasmic inclusions in almost all cases of amyotrophic lateral sclerosis and ∼60% of frontotemporal lobar degeneration cases. We have found that increased expression of the autophagy protein SQSTM1/p62 induces the localization of wild type or mutant TD-P43+ to the cytoplasm in motor-neuron like cells (60-80% cytoplasmic) and we found that this requires the UBA domain of SQSTM1/p62 (30% cytoplasmic). Intriguingly, mutations in SQSTM1/p62 affecting the UBA domain and other regions of the protein have been linked with the ALS-FTD spectrum. This project will determine whether mutations affecting regions outside of the UBA domain also affect TDP-43 localisation (confocal microscopy) and whether altered localization due to SQSTM1/p62 expression affects cell viability (MTT assays). We will also perform a preliminary screen of autophagy modulators to determine the effect on endogenous SQSTM1/p62 expression and clearance of exogenously expressed TDP-43 (using microscopy and western blot analyses). 

Contact:

Dr Sarah Rea - sarah.rea@perkins.uwa.edu.au 
0404 087 434
Professor Nigel Laing - nigel.laing@perkins.uwa.edu.au 

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