Quick Project Snapshot

Presynaptic dysfunction in neurodevelopmental disorders

Neurodevelopmental disorders are a devastating group of conditions characterised by developmental impairments, which usually manifest in infants and children. These disorders can result in a broad range of deficits, including learning delay and intellectual disability, problems with muscle control and movement, and behavioural and emotional issues. In severe cases the affected individuals may require lifetime care and/or have a reduced life expectancy.

Gene technology is now enabling the identification of many novel causes of neurodevelopmental disorder. This provides a new starting point for understanding the relationships between specific genetic mutations, brain function and development, cognition and mental health. There is growing evidence that the machinery that controls the release of neurotransmitters is compromised in a range of neurodevelopmental disorders, including intellectual disability, epilepsy, and autism spectrum disorders.

 

We have recently identified the first human mutation in synaptotagmin-1 (Syt1), in a child with a severe neurodevelopmental disorder. The child harbouring this mutation displayed profound intellectual disability, delayed motor development, and severe neurophysiological disturbance, but MRI revealed no structural brain abnormality. This mutation (I368T) occurs in a highly conserved residue in Syt1. We examined the effect of I368T Syt1 on presynaptic activity, and found that the presence of this mutant variant of Syt1 in neurons resulted in altered synaptic vesicle recycling dynamics.

We have now identified a further 5 mutations in Syt1, in individuals who have symptoms that largely overlap with our index case, but with differing degrees of severity.

Project: Investigate how mutations in Syt1 affect the synaptic vesicle cycle, and whether these effects are treatable: This project will examine whether all Syt1 mutations cause the same alterations to neurotransmitter release dynamics, thereby determining the molecular mechanisms underlying neurodevelopmental disorders in individuals harbouring these mutations. Intriguingly, mutations in the related protein, synaptotagmin-2, cause a neuromuscular disorder which is treatable. We will investigate whether pharmacological intervention with this same drug can at least partially overcome some of the deficits caused by mutations in Syt1.

This project will implement a variety of techniques, including molecular biology, biochemistry, primary neuronal cell culture, fixed immunofluorescence imaging and live-cell fluorescent imaging, giving students the opportunity to master a range of key transferrable skills. 

CO-HEAD OF DIVISION

Professor Philip Beart

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CO-HEAD OF DIVISION

Prof Colin Masters

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Biophysics Laboratory

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HEAD OF LAB
Dr Simon Drew

Prana Laboratory

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Dr Robert Cherny

Neurodegeneration

Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease and the incidence of Parkinson’s Disease is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.

All Labs that operate in this Division

Atomic Pathology LaboratoryBiophysics LaboratoryCellular Neurodegeneration LaboratoryCreutzfeldt Jakob Disease Clinical Research GroupMolecular Gerontology LaboratoryMotor Neurone Disease LaboratoryNational Dementia Diagnostics LaboratoryNeurochemistry of Metal IonsNeurogenesis and Neural Transplantation LaboratoryNeuropathology and Neurodegeneration LaboratoryNeuroproteomics and Metalloproteomics LaboratoryNeurotherapeutics LaboratoryParkinson's Disease LaboratoryPrana LaboratoryPre-clinical Parkinson’s Disease Research LaboratoryPresynaptic Physiology Stem Cells and Neural Development LaboratorySteroid Neurobiology LaboratorySynaptic Neurobiology LaboratoryThe Australian Imaging Biomarker and Lifestyle Study (AIBL)