Dr Gonzalo Perez-Siles

Research Fellow - Concord Clinical SchoolSenior Hospital Scientist - The ANZAC Research Institute

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Research interests

My research at the Northcott Neuroscience Laboratory, ANZAC Research Institute focuses on understanding the underlying pathogenic biology causing inherited peripheral neuropathies (IPNs). Specifically, my work aims to create relevant cell and animal models for developing treatment therapies for IPNs. As a Postdoctoral Fellow, I lead the mouse and the cell biology program at the Northcott Neurobiology Laboratory. My research interests or areas of expertise include:

- Developing animal models for the study of axonal degeneration in IPNs. I have recently completed the characterization of a conditional knock mouse to model X-linked distal hereditary motor neuropathy, dHMNX. This mouse model allows investigation of the subtle defects in copper metabolism and transport within the nervous system.

- Cell biology and molecular biology: the use of patient derived fibroblasts constitutes a fundamental aspect of my research. In particular, my investigations using primary fibroblasts from Charcot Marie Tooth type X6 (CMTX6) patients highlights a potential target for therapeutic intervention and treatment of this disease. I am responsible of implementing induced pluripotent stem cell (iPSC) technology in our laboratory. We are using this technology to differentiate patient motor neurons harbouring the disease causative mutations (CMTX6 and other IPNs) to generate human neuronal models for these diseases.

- I have a great interest for teaching new staff and co-supervising postgraduate students. In the last 5 years, I have participated in officially supervising 10 students including Honours, Masters and PhD students from The University of Sydney, UTS and International students.

Teaching and supervision

• Co-supervision of UTS Faculty of Science Honours student Rebecca Screnci. “Using patient-derived iPSC to model axonal degeneration cause by the R158H mutation in PDK3”. July 2016 - April 2018 (First Class Honours Awarded).
• Co-supervision of International Masters student Giulia del Rosso. “Exploration of cellular pathways triggering axonal degeneration in a conditional knock in mouse model for X-linked distal hereditary motor neuropathy (Atp7aT985I)”. March 2017 - November 2017.
• Co-supervision of Masters student Anna Siddell. “Unraveling the pathogenic molecular mechanisms of Morc2 mutations causing Charcot-Marie-Tooth type 2Z”. August 2014 - July 2016.
• Supervision of undergraduate students on the Sydney Medical School Summer Research Scholarship program:
- 2017: Kimberley Harvey and Grace Heloise Attrill (Co-supervisor).
- 2016: Jessica Falon. Second prize on the Summer Research Scholarships Dean’s Prize Awards.
- 2012: Roshini Ramkumar (Co-supervisor).
- 2013: Michael Erick Efendy (Co-supervisor).

Current research students

Project title Research student
Correcting GJB1 gene dysregulation in X-linked Charcot-Marie-Tooth neuropathy Bianca GROSZ

Current projects

The lack of effective treatments for IPNs is in part due to the absence of relevant human neuronal models that can be utilised for bridging the currently existing gap between in vitro studies and clinical application. We are currently growing motor neurons and peripheral nerves from induced pluripotent stem cells (iPSC) derived from a variety of IPN patients which disease causing mutations had been previously identified in our gene discovery program.

Among the iPSC lines we have stablished at the Northcott Laboratory I am particularly interested in identifying pathomechanisms leading to degeneration of axons in motor neurons derived from 2 subtypes of IPN patients:

- X-linked Charcot Marie Tooth type 6 (CMTX6), caused by mutations in the pyruvate dehydrogenase kinase 3 gene (PDK3), represents a unique opportunity to perform screening of molecules that can revert a known pathogenic signature in patient derived motor neurons. By using motor neurons derived from CMTX6 patients we are currently in the position to assist in the development of future treatment strategies for these intractable diseases.

- X-linked distal hereditary motor neuropathy (dHMNX), caused by mutations in the ATP7A gene, a P-type ATPase essential for cellular copper (Cu) transport and homeostasis. dHMNX is a non-fatal form of motor neuron disease (MND). Understanding how Cu dysregulation leads to axonal degeneration of motor neurons will facilitate development of Cu based treatment therapies.

Awards and honours

• ASSCR/NSCFA travel award (National Stem Cell Foundation of Australia). 2018
• CASS Foundation Travel Award. 2017
• Concord Repatriation General Hospital (CRGH) Travel Grant, 2016.
• Concord Repatriation General Hospital (CRGH) Research Awards (Early Career Researcher category), 2016.
• International Charcot-Marie-Tooth and Related Neuropathy Consortium (CMTR) Meeting, Scientific Committee Travel Grant, 2016.
• SyNRG Meeting (Sydney Neuropathy Research Group). Early Career Researcher Award, 2015.
• Peripheral Nerve Society Meeting Travel Award, 2015.
• Developmental Neurobiology (Okinawa Institute of Science and Technology). Travel Award, 2011.

Selected publications

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Journals

  • Perez-Siles, G., Grant, A., Ellis, M., Ly, C., Kidambi, A., Khalil, M., Llanos, R., La Fontaine, S., Strickland, A., Zuchner, S., Bermeo, S., Neist, E., Speranza, T., Nicholson, G., Kennerson, M., et al (2016). Characterizing the molecular phenotype of an: Atp7aT985I conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX). Metallomics, 8(9), 981-992. [More Information]
  • Perez-Siles, G., Ly, C., Grant, A., Drew, A., Yiu, E., Ryan, M., Chuang, D., Tso, S., Nicholson, G., Kennerson, M. (2016). Pathogenic mechanisms underlying x-linked charcot-marie-tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. Neurobiology of Disease, 94, 237-244. [More Information]

2016

  • Perez-Siles, G., Grant, A., Ellis, M., Ly, C., Kidambi, A., Khalil, M., Llanos, R., La Fontaine, S., Strickland, A., Zuchner, S., Bermeo, S., Neist, E., Speranza, T., Nicholson, G., Kennerson, M., et al (2016). Characterizing the molecular phenotype of an: Atp7aT985I conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX). Metallomics, 8(9), 981-992. [More Information]
  • Perez-Siles, G., Ly, C., Grant, A., Drew, A., Yiu, E., Ryan, M., Chuang, D., Tso, S., Nicholson, G., Kennerson, M. (2016). Pathogenic mechanisms underlying x-linked charcot-marie-tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. Neurobiology of Disease, 94, 237-244. [More Information]

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