Dr Karen Smillie

Personal profile

• 2014  -present: Lecturer, University of Edinburgh
• 2009 - 2015 Post-doctoral Research Fellow, Prof. M. Cousin Lab, University of Edinburgh
• 2005 - 2009 Post-doctoral Research Associate, Prof. E. Smythe Lab, University of Sheffield
• 2001 - 2005 PhD Prof. M.Cousin Lab, University of Edinburgh
• 1997 - 2001 BSc (Hons) Biochemistry, University of Edinburgh

Research Theme

• Synapses, Circuits and Behaviour
• Ageing and Degeneration      

Research

Neurodegeneration can be caused by a failure of neurons to efficiently and accurately communicate with one another at structures called synapses and this is a hallmark of many conditions, including Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and prion related diseases called synaptopathies.  By investigating the molecular mechanisms governing the early events leading to synaptic failure, we may be able to prevent or at least slow the progression of synaptic failure.  My research uses Huntington’s Disease as a model to examine this.

Huntington’s disease (HD) is a late onset neurodegenerative disease with no known cure.  The main symptoms of this debilitating condition are uncontrolled writhing movements, cognitive decline and altered psychological behaviour.  These symptoms reflect neuronal death especially in the striatum and cortex of HD sufferers.  HD is an autosomal dominant inherited disorder caused by mutation of a single gene, huntingtin.  The unaffected version of the gene has 10-26 copies of the trinucleotide repeat CAG (coding for glutamine) and affected individuals have an expansion of this region with at least 40 copies.  The resulting huntingtin protein has an expanded stretch of polyglutamine residues altering the conformation, structure and binding properties of this protein, potentially leading to altered function and neuronal toxicity.   

My research uses a knock-in mouse model of HD (Q140) which expresses the expanded form of the huntingtin protein with approximately 140 repeats.  We culture hippocampal, striatal (figure 1), cortical and cerebellar granule neurons from these mice and investigate the presynaptic mechanisms involved in neurotransmitter release and synaptic vesicle recycling.  We do this through biochemical assays, fluorescent imaging of real-time vesicle recycling and electron microscopy. 

My research also uses induced pluripotent stem cells from patients with HD (figure 2).  We are currently characterising these cells and will be using them in parallel with the mouse cultures to investigate presynaptic dysfunction in a human model of HD.  Together, the findings from these models will provide important insights into the cause of neuronal degeneration in this devastating condition and potentially provide information which is applicable to neurodegeneration more broadly.    

Image

Funding

Cure Huntington’s Disease Initiative

Group members

• Hamish Runciman, PhD student

Collaborations

• Prof. Mike Cousin (University of Edinburgh, UK)
• Prof. Paul Kemp (University of Cardiff, UK)
• Prof. Nick Allen (University of Cardiff, UK)
• Dr Sarah Gordon (Florey Institute of Neuroscience and Mental Health, Melbourne, Australia)

Selected publications

1. Smillie KJ, Cousin MA, Gordon SL. (2021) Presynaptic dysfunction and disease. J Neurochem.; accepted manuscript in press.
2. Harper CB, Smillie KJ. (2021) Current molecular approaches to investigate presynaptic dysfunction.  J Neurochem.; online ahead of print doi: 10.1111/jnc.15316.
3. Cousin MA, Smillie KJ. (2021)  Monitoring activity-dependent bulk endocytosis in primary neuronal culture using large fluorescent dextrans.  Methods Mol Biol.; 2233:101-111.
4. Harper CB, Small C, Davenport EC, Low DW, Smillie KJ, Martinez-Marmol R, Meunier FA, Cousin MA. (2020) An epilepsy-associated SV2A mutation disrupts synaptotagmin-1 expression and activity-dependent trafficking.  J Neurosci.; 40(23):4586-4595.
5. McAdam RL, Morton A, Gordon SL, Alterman JF, Khvorova A, Cousin MA, Smillie KJ. (2020) Loss of huntingtin function slows synaptic vesicle endocytosis in striatal neurons from the httQ140/Q140 mouse model of Huntington's disease. Neurobiol Dis.; 134:104637.
6. Kokotos AC, Harper CB, Marland JRK, Smillie KJ, Cousin MA, Gordon SL. (2019) Synaptophysin sustains presynaptic performance by preserving vesicular synaptobrevin-II levels. J Neurochem.; 151(1):28-37.
7. Cousin MA, Gordon SL, Smillie KJ. (2018) Using FM Dyes to Monitor Clathrin-Mediated Endocytosis in Primary Neuronal Culture. Methods Mol Biol.; 1847:239-249.
8. Nicholson-Fish JC, Smillie KJ, Cousin MA. (2016) Monitoring activity-dependent bulk endocytosis with the genetically-encoded reporter VAMP4-pHluorin. J Neurosci Methods doi: 10.1016/j.jneumeth.2016.03.011.
9. Gordon SL, Harper CB, Smillie KJ, Cousin MA. (2016) A Fine Balance of Synaptophysin Levels Underlies Efficient Retrieval of Synaptobrevin II to Synaptic Vesicles. PLoS One; 11(2):e0149457.
10. Marland JR, Smillie KJ, Cousin MA. (2016) Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome. PLoS One; 11(2):e0147974.
11. Nicholson-Fish JC, Cousin MA, Smillie KJ. (2016) Phosphatidylinositol 3-Kinase Couples Localised Calcium Influx to Activation of Akt in Central Nerve Terminals. Neurochem Res.;41(3):534-43.
12. Nicholson-Fish JC, Kokotos AC, Gillingwater TH, Smillie KJ, Cousin MA. (2015) VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis. Neuron 88(5):973-84.
13. Kavanagh DM, Smyth AM, Martin KJ, Dun A, Brown ER, Gordon S, Smillie KJ, Chamberlain LH, Wilson RS, Yang L, Lu W, Cousin MA, Rickman C, Duncan RR. (2014) A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion. Nat Commun.;5:5774.
14. Smillie KJ, Pawson J, Perkins EM, Jackson M, Cousin MA. (2013) Control of synaptic vesicle endocytosis by an extracellular signalling molecule. Nat Commun. 4:2394.
15. Smillie KJ, Cousin MA. (2012) Akt/PKB controls the activity-dependent bulk endocytosis of synaptic vesicles. Traffic. 13(7):1004-11.
16. Quan A, Xue J, Wielens J, Smillie KJ, Anggono V, Parker MW, Cousin MA, Graham ME, Robinson PJ. (2012) Phosphorylation of syndapin I F-BAR domain at two helix-capping motifs regulates membrane tubulation. Proc Natl Acad Sci U S A.;109(10):3760-5.
17. Xue J, Graham ME, Novelle AE, Sue N, Gray N, McNiven MA, Smillie KJ, Cousin MA, Robinson PJ. (2011) Calcineurin Selectively Docks With The Dynamin Ixb Splice Variant To Regulate Activity-Dependent Bulk Endocytosis. J Biol Chem.;286(35):30295-303.
18. Smillie KJ, Cousin MA.(2011) The Role of GSK3 in Presynaptic Function. Int J Alzheimers Dis. 14;2011:263673.
19. Clayton EL, Sue N, Smillie KJ, O'Leary T, Bache N, Cheung G, Cole AR, Wyllie DJ, Sutherland C, Robinson PJ, Cousin MA. (2010) Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles. Nat Neurosci. 13(7):845-51.
20. Clayton EL, Anggono V, Smillie KJ, Chau N, Robinson PJ, Cousin MA. (2009) The phospho-dependent dynamin-syndapin interaction triggers activity-dependent bulk endocytosis of synaptic vesicles. J Neurosci. 17;29(24):7706-17.
21. Anggono V, Smillie KJ, Graham ME, Valova VA, Cousin MA, Robinson PJ.(2006) Syndapin I is the phosphorylation-regulated dynamin I partner in synaptic vesicle endocytosis. Nat Neurosci. 9(6):752-60.
22. Smillie KJ, Evans GJ, Cousin MA. (2005) Developmental change in the calcium sensor for synaptic vesicle endocytosis in central nerve terminals. J Neurochem. 94(2):452-8.
23. Smillie KJ, Cousin MA.(2005) Dynamin I phosphorylation and the control of synaptic vesicle endocytosis. Biochem Soc Symp.(72):87-97, 2005.
24. Cousin MA, Malladi CS, Tan TC, Raymond CR, Smillie KJ, Robinson PJ. (2003) Synapsin I-associated phosphatidylinositol 3-kinase mediates synaptic vesicle delivery to the readily releasable pool. J Biol Chem. 278(31):29065-71.
25. Pang S, Wang W, Rich B, David R, Chang YT, Carbunaru G, Myers SE, Howie AF, Smillie KJ, Mason JI.(2002) A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab. 87(6):2556-63.

Information for students:

Willingness to discuss research projects with undergraduate and postgraduate students: YES - please click here