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Northcott Neuroscience Laboratory, ANZAC Research Institute

The Northcott Neuroscience Laboratory, ANZAC Research Institute, is led by Group Leader, Professor Marina Kennerson. The laboratory is internationally renowned in the field of human hereditary neuropathies and motor neuron disorders and made important contributions to the discovery of gene mutations causing neurodegeneration of peripheral nerve and motor neurons. The discovery of gene mutations in our families collected by Professor Nicholson over the last 40 years, have uncovered new mechanisms causing disease. As part of our gene discovery and translational genomics program, we are developing both in vitro and in vivo pre-clinical models to facilitate developing therapies for this group of intractable diseases. Our laboratory is truly translational and focuses on determining the underlying causes of neurodegenerative disease firstly to develop diagnostic tools and eventually to develop effective treatment therapies.

Gene Discovery

Our key focus for gene discovery has been studying Charcot-Marie-Tooth (CMT) disease and related disorders. CMT is a degenerative disorder of the peripheral nerves affecting both sensory and motor nerves. Individuals who suffer from this disorder experience distal muscle weakness of legs and arms, foot deformities and sensory loss. Motor and sensory neurons are unique cells with long axons (up to 1 meter) that require continuous maintenance from the cell body to the nerve endings. The breakdown of this maintenance leads to the 'dying back' of the nerve ends (axonal degeneration). Our research aims to identify the biological pathways leading to axonal degeneration with the ultimate goal of developing treatments. To do this we identify the faulty gene in families with CMT disease.

Identifying genes for CMT disease entered an exciting era when next generation sequencing (NGS) expedited the gene discovery process. However, despite identifying over 120 genes causing CMT and related disorders, 30-40% of CMT patients remain genetically undiagnosed. Therefore, our quest continues to solve the genetic cause in these families.

The recent award of a MRFF Genomics Health Futures Mission Grant (2021-2025) which Professor Kennerson is co-leading with Professor Nigel Laing (University of WA) is centred around improving the diagnostic rate of adult neurodegenerative disease including CMT. This funding will be used to identify new genes and DNA re-arrangements causing CMT using whole genome sequencing.

In 2021 we have continued to focus on understanding how large DNA re-arrangements known as "structural variation" can cause the degeneration of motor and sensory neurons in patients. These DNA rearrangements can involve hundreds to millions of DNA bases. Our results have confirmed that copying and pasting large pieces of DNA where they are not supposed to be is affecting the expression of genes where the DNA has been inserted for two types of neuropathy, X-linked CMT type 3 (CMTX3) and distal hereditary motor neuropathy type 1 (DHMN1). The laboratory is now routinely growing these patient motor neurons to understand the effect of DNA re-arrangements on gene expression in the relevant tissue affected in patients.

Our work continues to study Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND) in Malaysia. With colleagues at the University of Malaya (Professor Nortina Shahrizaila and Associate Professor Azlina Ahmad-Annuar) the team has recruited and screened over 100 ALS patients for mutations in known genes that cause this disease. This research is providing a unique opportunity to generate new data on the role of genetic mutations in the pathogenesis of ALS in a multiethnic Southeast Asian region and will contribute towards new hypotheses of disease pathways, providing alternative avenues in the development of therapeutic treatments for this devastating disease.

Cell Biology Program

The cell biology program is led by Dr Gonzalo Perez-Siles for the study of mutations causing inherited peripheral neuropathies. Understanding the normal function and the consequences of the mutations in neuronal cell lines, will further our understanding of the mechanisms causing degenerative nerve disease. Dr Perez-Siles has successfully developed motor neuron models for our PDK3 and ATP7A gene discoveries which were published in 2020. Similarly, patient derived iPSC lines with the ATP7A mutation are proving to be valuable models to study copper transport in motor neurons.

Dr Anthony Cutrupi is establishing a cell biology program for Amyotrophic Lateral Sclerosis (ALS) with a focus on understanding the mechanisms of neurodegeneration in the context of aging which is a major risk factor for developing the disease. This program harnesses induced pluripotent stem cell technologies which he has been responsible for implementing at the ANZAC Research Institute.

Functional Genomics Program

As part of our genomics translational program for inherited neuropathies and motor neuron disorders we have been using Caenorhabditis elegans (C. elegans) as a model organism. C. elegans are a small (about 1 mm in length), transparent nematode with a short life cycle and a well characterised nervous system - making them ideal for studying axonal degeneration caused by the gene mutations discovered by our laboratory (PDK3 and ATP7A). In 2021 we published characterisation of the first knock in and overexpression model of the PDK3 gene mutation causing CMTX6. This project is led by Dr Ramesh Narayanan. The pre-clinical model he has developed will be used for downstream functional studies and therapeutic drug screens.

Our Key Achievements and Awards

Our Research Team

Professor Marina Kennerson Group Leader
Dr Kishore Kumar Clinical Collaborator
Dr Gonzalo Perez-Siles Postdoctoral Fellow
Dr Ramesh Narayanan Postdoctoral Fellow
Dr Anthony Cutrupi Postdoctoral Fellow
Dr Bianca Grosz Postdoctoral Fellow
Melina Ellis Research Assistant
Alexandra Boyling PhD Candidate
Dora Yasar Masters Student

Selected Grants

Amount awarded Grant and project details
$2,996,253 MRFF Genomics Health Futures Mission Stream 1 and 2, 2021-2025
Closing the gap in diagnosis of neurological disorders including ataxias and neuropathies – a trans-Australian collaboration
Investigators: Laing, Kennerson, Lamont, Vucic, Davis, Bryson-Richardson, Ravenscroft, Perez-Siles, Beecroft, Ghaoui
$783,420 National Health and Medical Research Council, 2020-2022
Looking Beyond the Exome: structural variation and gene dysregulation causing neurodegeneration.
Investigators: Kennerson, Perez-Siles, Narayanan

Our Publications

2023

Narayanan, Ramesh & Panwar, Ajay & Butler, Tim & Cutrupi, Anthony & Kennerson, Marina & Vucic, Steve & Balasubramaniem, Ashok kumar & Mangelsdorf, Marie & Wallace, Robyn. (2023). Transgenic mice overexpressing mutant TDP-43 show aberrant splicing of neurological disorders-associated gene Zmynd11 prior to onset of motor symptoms. microPublication biology. 2023 10.17912.