Parkinson's Disease Research
details here
Inherited Peripheral Neuropathies
Dr Marina Kennerson, Bartosz Kowalski, Dr Stephen Reddel, Megan Brewer, Rabia Chaudhry, Shannon Chu, Prof Garth Nicholson
Charcot-Marie-Tooth (CMT) neuropathy is the most common group of human hereditary disorders. The syndrome is a disorder of peripheral nerve affecting both motor and sensory neurons. CMT is a disabling disorder that afflicts 8000 Australians for their lifetime. It, therefore, has major economic impacts in terms of productive years lost and the requirement for medical, paramedical and pension support, estimated to be $220 million per year.
Approximately 15% of all CMT is inherited on the X chromosome. The most common form of X-linked CMT (CMTX1), is caused by mutations in the connexin 32 (Cx32) gene. We have continued to screen candidate genes in a 5.7 megabase interval on chromosome Xq26.3-q27.1 which harbours the CMTX3 locus. A total of 25 annotated genes have been reported in the interval and 24 of the coding regions of these genes have been excluded for a pathogenic role in CMTX3. Through collaborations with our US colleagues, we have been able to obtain DNA samples from family that first reported the CMTX3 locus back in 1991. This resource will be extremely important for validating the CMTX3 gene mutation when it is eventually identified. The discovery of this gene will reveal mechanisms causing degeneration of long nerves. Finding new mechanisms of length dependent axonal degenerations may provide insights relevant to other neurodegenerative disorders.
The mutation analysis of genes involved with CMT has been expedited by the introduction of a new improved method called High Resolution Melt (HRM) analysis. The LightScanner machine from Idaho Technology USA is the first instrument to be commissioned in an Australian research institute and was the first to be purchased in the world. We have validated this technology in our laboratory using the Cx32 gene and the method has been used to identify mutations in large multi-exon gene for the most common axonal form of CMT (CMT2A; mitofusin MFN2) and the dynamin 2 (DNM2) gene causing intermediate CMT (DI-CMTB). HRM analysis is a simple, sensitive and cost efficient method to alternative gene scanning methods and has the potential to reduce the sequencing burden of a gene discovery project.
back to top
Motor Neuron Disease (MND/ALS)
This study is displayed on its own page, link here to view details MND/ALS Reseach
back to top
Cell Biology Research Program
Dr Simon Myers, Martin Simone
The major objective in our projects is to investigate and understand the functional cellular and molecular mechanisms of neuro-degenerative diseases.
Dominant Intermediate Charcot-Marie-Tooth Neuropathy
Mutations have been identified in the dynamin 2 (Dyn2) which cause dominant-intermediate Charcot-Marie-Tooth (DI-CMTB) syndrome, an autosomal hereditary neuropathy. We have shown in DI-CMTB patient lymphoblast cells that the mutant Dyn2 blocks receptor mediated endocytosis (in collaboration with Prof. P Robinson and Dr. C Malladi from the Children’s Medical Research Institute). We have also observed in this disease that the cells have very altered morphology as depicted by scanning electron microscopy.
Hereditary Sensory NeuropathyHereditary sensory neuropathy type 1 (HSN1) is one of the most common and best characterised form of peripheral sensory neuron degeneration. Clinically, it is characterised by loss of pain sensation, muscle wasting and weakness. Mutations in the serine palmitoyltransferase long chain subunit 1 (SPTLC1) protein cause HSN1. Pilot studies over-expressing the mutant SPTLC1 gene in human neuronal cells showed altered localisation of the SPTLC1 and changes to the actin cytoskeleton. We have also shown that the HSN patient lymphoblasts do not have blocked receptor-mediated endocytosis. Further investigations will elucidate how these changes attribute to neuronal cell dysfunction in this neurodegenerative disease. Another exciting area for this program was the successful construction and generation of the HSN1 transgenic mouse. We are currently expanding this colony and have commenced characterisation of these animals for the HSN1 phenotype.
back to top
Parkinson's Disease Research
This study is displayed on its own page, link here to view details Parkinson's Disease Research
back to top
Research Programs