Sarah ReaDr Sarah Rea

Team Leader of ALS, Dementia and PDB functional genomics group
T: +61 8 9346 4430

Dr Sarah Rea completed a Bachelor of Science with Honours in Molecular Biology and Biomedical Science at Murdoch University in 2004. She worked as a Research Assistant in Professor Thomas Ratajczak’s Laboratory at the University of Western Australia, before completing her PhD investigating the genetics and functional genomics of Paget’s disease of bone. During this time she identified novel mutations in the SQSTM1/p62 gene as a cause of familial Paget’s disease, and determined the prevalence of SQSTM1/p62 mutations in a large well-characterised cohort of patients with familial or sporadic Paget’s (JBMR 2006, 2009). This work included genotype/phenotype analysis. Her work was the first to show that the normal version of SQSTM1/p62 has inhibitory roles in cell signalling and osteoclastogenesis, and this function is lost with mutations. Dr Rea was involved in a Genome-wide association study, that identified 7 novel loci to be associated with Paget’s disease (Nature Genetics, 2011).

Through her Raine Priming Grant, she was able to determine that dysfunctional proteostasis (autophagy) contributes to Paget’s pathobiology. During this time, she also led the Molecular Genetics group in Australia, and was responsible for mutational screening analysis of hundreds of participants enrolled in the Zoledronate in Prevention of Paget’s disease of bone clinical trial.

In 2013 Dr Rea was awarded an Alzheimer’s Australia Postdoctoral Research Fellowship, where she expanded her studies to SQSTM1/p62 variants linked to motor neuron disease/Amytrophic Lateral Sclerosis and Frontotemporal dementia.

Currently, Sarah is a National Health and Medical Research and Australian Research Council Dementia Fellow and Team Leader of the ALS, Dementia and PDB functional genomics group within the Laboratory for Neurogenetic Diseases headed by Winthrop Professor Nigel Laing. She is currently investigating the functional genomics of autophagy gene defects in relation to motor neuron disease and dementia and maintains a research focus on determining novel underlying genetic factors of Paget’s disease.

Sarah has been an active committee member of the Combined Biological Sciences Meeting, with the role of secretary for the past 3 years. This meeting focuses on bringing scientists from varied disciplines together to share ideas and form collaborations and also to inspire students.

Research overview

  • Understanding the mechanisms of disease in ALS, dementia and PDB
  • Identifying therapeutic targets for ALS and dementia
  • Genetic causes of Paget’s disease of bone

Research Projects

  • Identification of common underlying pathways of pathogenesis in ALS/FTD caused by autophagy gene defects.
  • Identifying autophagy modulators that clear pathogenic proteins in ALS
  • Application of next generation sequencing to identify genetic causes of Paget’s disease of bone to enable genetic screening of family members and offer preventative treatment.

Selected Publications

  1. Rea SL, Walsh JP, Ward L, Magno AL, Ward BK, Shaw B, Layfield R, Kent GN, Xu J, Ratajczak T. Sequestosome 1 mutations in Paget's disease of bone in Australia: prevalence, genotype/phenotype correlation, and a novel non-UBA domain mutation (P364S) associated with increased NF-kappaB signaling without loss of ubiquitin binding. J Bone Miner Res. 2009. 24(7):1216-23. PMID: 19257822 2.
  2. Rea SL, Walsh JP, Ward L, Yip K, Ward BK, Kent GN, Steer JH, Xu J, Ratajczak T. A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappaB signaling and Paget's disease of bone with a severe phenotype. J Bone Miner Res. 2006 21(7):1136-45. PMID: 16813535 3.
  3. Rea SL, Majcher V, Searle MS, Layfield R. SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD. Exp Cell Res. 2014. 1;325(1):27-37. Review. PMID: 24486447 4.
  4. Wright T*, Rea SL*, Goode A, Bennett AJ, Ratajczak T, Long JE, Searle MS, Goldring CE, Park BK, Copple IM, Layfield R. The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone. Bone. 2013 Feb;52(2):699-706. PMID: 23117207. *equal 1st author. 5.
  5. Rea SL, Walsh JP, Layfield R, Ratajczak T, Xu J. New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget's disease of bone. Endocr Rev. 2013 Aug;34(4):501-24. Review. PMID: 23612225 6.
  6. Albagha OM, Wani SE, Visconti MR, Alonso N, Goodman K, Brandi ML, Cundy T, Chung PY, Dargie R, Devogelaer JP, Falchetti A, Fraser WD, Gennari L, Gianfrancesco F, Hooper MJ, Van Hul W, Isaia G, Nicholson GC, Nuti R, Papapoulos S, Montes Jdel P, Ratajczak T, Rea SL, Rendina D, Gonzalez-Sarmiento R, Di Stefano M, Ward LC, Walsh JP, Ralston SH; Genetic Determinants of Paget's Disease (GDPD) Consortium. Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nat Genet. 2011. 29;43(7):685-9. PMID: 21623375 7.
  7. Ang E, Pavlos NJ, Rea SL, Qi M, Chai T, Walsh JP, Ratajczak T, Zheng MH, Xu J. Proteasome inhibitors impair RANKL-induced NF-kappaB activity in osteoclast-like cells via disruption of p62, TRAF6, CYLD, and IkappaBalpha signaling cascades. J Cell Physiol. 2009. 220(2):450-9. PMID: 19365810 8.
  8. Ying H, Qin A, Cheng TS, Pavlos NJ, Rea S, Dai K, Zheng MH. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent. PLoS One. 2015 Apr 30;10(4):e0125696. PMID: 25928135 9.
  9. Goode A, Long JE, Shaw B, Ralston SH, Visconti MR, Gianfrancesco F, Esposito T, Gennari L, Merlotti D, Rendina D, Rea SL, Sultana M, Searle MS, Layfield R. Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function. Biochim Biophys Acta. 2014. 1842(7):992-1000. PMID: 24642144 10.
  10. Albagha OM, Visconti MR, Alonso N, Wani S, Goodman K, Fraser WD, Gennari L, Merlotti D, Gianfrancesco F, Esposito T, Rendina D, di Stefano M, Isaia G, Brandi ML, Giusti F, Del Pino-Montes J, Corral-Gudino L, Gonzalez-Sarmiento R, Ward L, Rea SL, Ratajczak T, Walsh JP, Ralston SH. Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease. J Bone Miner Res. 2013 Nov;28(11):2338-46. J Bone Miner Res. 2013. 28(11):2338-46. doi: 10.1002/jbmr.1975. PMID: 23658060
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