Jane Rylett, PhD


Jane Rylett, Co-Director, Molecular Brain Research

Why I Became a Scientist

I have always been fascinated by how things are put together and how they work. As an undergraduate student, I developed an interest in changes that occur in cells during aging and the effects on brain function. This provided me with a model to be able to focus my questions around mechanisms involved in neurotransmission and impacts of aging. As a graduate student, I was exposed to Alzheimer disease by becoming involved in new drug trials in Alzheimer patients as a side-line to the cellular – mechanistic studies of my thesis research. This provided me with insight into the human and potential translational aspect of my research. This was a life-changing experience as I saw the struggles of the patients and their caregivers, and the enormous impact that neurodegenerative diseases can have on our aging population. It seemed natural to develop a research program studying the mechanisms by which nerve cells communicate information and the impact that changes that occur in aging and disease have on these processes. I have been very fortunate to be able to combine my passion for investigating these topics with an involvement in outreach activities in the Alzheimer community. This involves volunteer service in local, provincial and national Alzheimer Societies, and serving as an advocate for the value or science and research in finding a cure. I can’t imagine a more exciting or fulfilling career choice.

Research Summary

Research in my laboratory focuses on mechanisms regulating chemical communication in the nervous system in health, normal aging and disease. Much of the research that we carry out involves studies of the function of cholinergic neurons. In brain, these neurons project from basal forebrain nuclei to neocortex and hippocampus playing important roles in cognitive processes such as learning and memory, while cholinergic neurons in striatum are involved in movement and motor functions. Degeneration of basal forebrain cholinergic neurons underlie a number of age-related neurological disorders such as Alzheimer disease and some of the cognitive deficits associated with normal aging. Dysfunction of cholinergic neurons in the striatum occurs in movement disorders such as Huntington's chorea, and imbalance between dopaminergic and cholinergic transmission is found in Parkinson's disease and drug-induced disorders such as tardive dyskinesia. Current research interests in my laboratory include the physiological mechanisms controlling events in the synthesis of the neurotransmitter acetylcholine, the mechanisms by which amyloid peptides cause neuron dysfunction and degeneration and the role that growth and trophic factors may play in regulation of the expression of cholinergic neuronal phenotype and in maintenance and survival of these neurons. Specific projects relate to characterization and regulation of the neuronal choline transport protein and enzyme choline acetyltransferase, and investigation of regulation of delivery of choline and metabolism for acetylcholine synthesis. A range of cellular and molecular biological approaches are used in these investigations, including genomics and proteomics, protein trafficking and molecular imaging, protein chemistry, protein-protein interactions and signal transduction.

Research Questions and Disease Implications

How do amyloid peptides impact cholinergic neuron function early in mild cognitive impairment and Alzheimer disease? How can this be prevented?

What role does maintaining competent cholinergic neurotransmission play in altering the course of development of mild cognitive impairment and Alzheimer disease?

Do certain forms of cholinergic proteins serve a neuroprotective function by regulating amyloid metabolism?

Education

  • B.Sc. (Honours) Physiology and Pharmacology, The University of Western Ontario 
  • Ph.D. Pharmacology, The University of Western Ontario

Training

  • Postdoctoral Fellowship, Department of Pharmacology, University College London, University of London, London, England [Medical Research Council of Canada Fellowship]
  •  Visiting Scientist, Abteilung Neurochemie, Max-Planck-Institute fur Biophysical Chemistry, Gottingen, Germany

Awards

  • Bell Canada Centennial Fellowship 
  • Medical Research Council Fellowship 
  • J.B. Collip Medal for Medical Research 
  • Rubinoff Scholarship in Geriatrics 
  • Ontario Ministry of Health Career Scientist Award
  • European Molecular Biology Organization Fellowship 
  • Claude P. Beaubien Award for Research in Alzheimer Disease
  • AltaPharm Senior Scientist Award from the Pharmacological Society of Canada
  • Dean’s Award of Excellence in Research, Schulich School of Medicine & Dentistry, University of Western Ontario
  • Queen Elizabeth II Golden Jubilee Medal [Governor General of Canada]

Publications

  • Resendes MC, Dobransky T, Ferguson SSG and Rylett RJ (1999) Nuclear localization of the 82 kDa form of human choline acetyltransferase. Journal of Biological Chemistry, 274: 19417-19421.
  • Dobransky T, Davis W, Xiao GH and Rylett RJ (2000) Characterization and phosphorylation of recombinant 69 and 82 kDa human choline acetyltransferase. Biochemical Journal, 349: 141-151
  • Dobransky T, Davis WL and Rylett RJ (2001) Functional characterization of phosphorylation of 69 kDa human choline acetyltransferase at serine-440 by protein kinase C. Journal of Biological Chemistry, 276: 22244-22250.
  • Kalisch BE, Bock NA, Davis WL and Rylett RJ (2002) Inhibitors of nitric oxide synthase prevent nerve growth factor-mediated increases in cholinergic gene expression in PC12 cells. Journal of Neurochemistry, 81: 624-635. 
  • Baskey JC, Kalisch BE, Davis WL, Meakin SO and Rylett RJ (2002) nnr5 cells expressing TrkA receptors undergo morphological but not cholinergic phenotypic differentiation in response to NGF. Journal of Neurochemistry, 80: 501-511.
  • Kalisch BE, Demeris CS, Ishak M and Rylett RJ (2003) Modulation of nerve growth factor-induced activation of MAP kinase in PC12 cells by inhibitors of nitric oxide synthase. Journal of Neurochemistry, 87: 1321-1332.
  • Dobransky T, Brewer D, Lajoie G and Rylett RJ (2003) Phosphorylation of 69 kDa choline acetyltransferase at threonine-456 in response to amyloid-β peptide 1-42. Journal of Biological Chemistry, 278: 5883-5893.
  • Dobransky T and Rylett RJ (2003) Functional regulation of choline acetyltransferase by phosphorylation. Neurochemical Research, 28: 537-542.
  • Gill SK, Bhattacharya M, Ferguson SSG and Rylett RJ (2003) Identification of a novel nuclear localization signal common to 69- and 82-kDa human choline acetyltransferase. Journal of Biological Chemistry, 278: 20217-20224.
  • Dobransky T, Doherty-Kirby A, Kim AR, Lajoie G and Rylett RJ (2004) Protein kinase-C isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. Journal of Biological Chemistry, 279: 52059-52068
  • Ribeiro F, Black SAG, Cregan SP, Prado VF, Prado MA, *Rylett RJ and *Ferguson SSG (2005) Constitutive high-affinity choline transporter endocytosis is determined by a carboxyl-terminal tail dileucine motif. Journal of Neurochemistry, 94: 86-96.  *co-corresponding authors
  • Kim AR, Doherty-Kirby A, Lajoie G, Rylett RJ and Shilton BH (2005) Two methods for large-scale purification of recombinant human choline acetyltransferase. Protein Expression and Purification, 40: 107-117
  • Gill SK, Ishak M and Rylett RJ (2005) Exposure of low-abundance nuclear antigens in formalin-fixed, paraffin-embedded necropsy human spinal cord tissue for immunohistochemical analysis. Journal of Neuroscience Methods, 148: 26-35.
  • Dobransky T and Rylett RJ (2005) A model for dynamic regulation of choline acetyltransferase by phosphorylation. Journal of Neurochemistry 95: 305-313. 
  • Kim AR, Dobransky T, *Rylett RJ and *Shilton BH (2005) Crystallization of human choline acetyltransferase by surface entropy reduction. Acta Crystallographica D 61: 1306-1310.  *co-corresponding authors
  • Kim AR, *Rylett RJ and *Shilton BH (2006) Substrate binding and catalytic mechanism of human choline acetyltransferase. Biochemistry 45: 14621-14631. *co-corresponding authors
  • Gill SK, Ishak M, Dobransky T, Haroutunian V, Davis K and Rylett RJ (2007) 82-kDa choline acetyltransferase is in nuclei of cholinergic neurons in human CNS and altered in aging and Alzheimer disease. Neurobiology of Aging 28: 1028-1040.
  • Ribeiro F, Pinthong M, Black SAG, Prado V, Prado MAM, Rylett RJ and Ferguson SSG (2007) Regulated recycling and plasma membrane recruitment of the high-affinity choline transporter. European Journal of Neuroscience 26: 3437-3448.
  • Pinthong M, Black SAG, Ribeiro FM, Pholpramool C, Ferguson SSG and Rylett RJ (2008) Activity and subcellular trafficking of the sodium-coupled choline transporter CHT is regulated acutely by peroxynitrite. Molecular Pharmacology 73: 801-812. 
  • Hristova VA, Beasley SA, Rylett RJ and Shaw GS (2009) Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. Journal of Biological Chemistry, 284: 14978-14986.
  • Young KF and Rylett RJ (2009) Oligomeric aggregates of amyloid-β peptide 1-42 activate ERK/MAPK in SH-SY5Y cells via the α7 nicotinic receptor. Neurochemistry International, 55: 796-801.

Contact Information

Tel: 519931-5777 ext. 24078

Email: Jane.Rylett@schulich.uwo.ca