Personal profile
- 2019 – present: MND Scotland research committee member
- 2016 – present: Editorial Board Member Scientific Reports
- 2016 – present: MRC Harwell panel member
- 2013 - present: Senior Lecturer, University of Edinburgh
- 2010 - 2013: Lecturer, University of Edinburgh
- 2005 - 2010: RCUK Fellowship in Neuroscience, University of Edinburgh
- 2002 - 2005: Caledonian Research Fellowship, University of Edinburgh
- 1998 - 2001: Postdoctoral Research Fellow, Johns Hopkins University
- 1994 - 1997: DPhil, Institute of Molecular Medicine, University of Oxford
- 1990 - 1994: BSc (Hons) Molecular Biology, University of Edinburgh
Research
Dr Mandy Jackson's research briefing
Causal genetic mutations have been identified for twenty-six subtypes of SCA and recently mutations in the gene SPTBN2, which encodes β-III spectrin, were identified as the genetic cause of SCA5 (Ikeda et al., 2006). We know from my previous work that β-III spectrin interacts with and increases EAAT4 cell surface expression, the glutamate transporter predominantly expressed in cerebellar Purkinje cells (Jackson et al., 2001). Sodium-dependent glutamate transporters remove glutamate from the synaptic cleft and neurotoxic levels of glutamate arise from the malfunction or aberrant expression of these proteins.
To further investigate the role of β-III spectrin in normal cerebellar development and SCA5 disease pathogenesis we have knocked-out the expression of β-III spectrin, creating an in vivo β-III spectrin deficient model. This has revealed that loss of β-III spectrin function leads to a splayed gait, progressive motor incoordination, tremor, and cerebellar degeneration, all characteristic features of cerebellar ataxia (Perkins et al., 2010). Analysis of this disease model has allowed us to identify sodium channel dysfunction and glutamate transporter loss, both neuronal (EAAT4) and astroglial (GLAST), as factors in disease pathogenesis. Disruption to the same physiological processes are also being implicated in models of other SCAs, highlighting convergence of common mechanisms in cerebellar ataxia.
Our current research directions focus on 1) elucidating what changes occur in the absence of wild type β-III spectrin or in the presence of β-III spectrin with mutations associated with SCA5; 2) identifying whether astrocytes play a role in Purkinje cell degeneration; 3) determining whether the disease phenotype can be rescued; 4) understanding the role β-III spectrin plays in normal Purkinje cell development and; 5) identifying other proteins that interact with β-III spectrin, thus highlighting other potential cellular pathways that could underlie neurodegeneration. A variety of techniques including genetic crosses, electrophysiology, cellular imaging, cell culture studies and yeast two-hybrid screens are being employed in the lab to achieve the research aims.
Team members
- Brenda Murage (PhD student)
Collaborations
- Prof Jeffrey Rothstein, John Hopkins University, Baltimore, Maryland, USA
- Prof David Wyllie, University of Edinburgh, UK
- Prof Andrea Nemeth, University of Oxford
- Dr Alastair Lyndon, Heriot-Watt University, Edinburgh, UK
- Dr Christos Gkogkas, University of Edinburgh, UK
- Dr Pleasantine Mill, University of Edinburgh, UK
- Dr Paul Skehel, University of Edinburgh, UK
- Professor Anthony Oro, Stanford University, USA
Recent Publications
BrownA, MeeraP, AltindagB, ChopraR, PerkinsE, PaulS, ScolesDR, TaraporeE, JacksonM, ShakkottaiVG, OtisTS, PulstSM, AtwoodSX, Oro AE (2018) MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias Proc Natl Acad Sci U S A. 115(52):E12407-E12416
PerkinsEM, ClarksonYL, SuminaiteD, LyndonAR, TanakaK, RothsteinJD, SkehelP, WyllieDJA, JacksonM (2018) Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells Hum. Mol. Genet. doi: 10.1093/hmg/ddy169. [Epub ahead of print]
Harmon M, Larkman P, Hardingham G, Jackson M & Skehel P (2017) A Bi-fluorescence complementation system to detect associations between the Endoplasmic reticulum and mitochondria Sci. Rep. 7:17467
Hall EA, Nahorsk MS, Murray LM, Shaheen R, Perkins E, Dissanayake KN, Kristaryanto Y, Jones RA4, Vogt J, Rivagorda M, Handley MT, Mali GR, Quidwai T, Soares DC, Keighren MA, McKie L, Mort RL, Gammoh N, Garcia-Munoz A, Davey T, Vermeren M, Walsh D, Budd P, Aligianis IA, Faqeih E, Quigley AJ, Jackson IJ, Kulathu Y, Jackson M, Ribchester RR, von Kriegsheim A, Alkuraya FS, Woods CG, Maher ER & Mill P (2017) Mutations in PLAA cause a lethal infantile epileptic encephalopathy by disrupting ubiquitin-mediated endolysosomal degradation of synaptic proteins Am. J. Hum. Genet. 100:706-724
Perkins EM, Suminaite D, Clarkson YL, Lee SK, Lyndon AR, Wyllie DJA, Rothstein JD, Tanaka K & Jackson M (2016). Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST Hum. Mol. Genet. Hum. Mol. Genet. 25:4448-4461
Perkins EM, Suminaite D, Jackson M (2016). Cerebellar ataxias: β- III spectrin’s interactions suggest common pathogenic mechanisms. J Physiol., 594:4661-76 [Editor’s choice & front cover image]
Schnekenberg RP, Perkins EM, Miller J, Davies WIL, D’Adamo MC, Pessia M, Fawcett K, Sims D, Gillard E, Hudspith K, Williams J, O’Regan M, Jayawant S, Jefferson R, Hughes S, Steinlin M, Lustenberger A, Ragoussis J, Jackson M, Tucker ST, Németh AH (2015). De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain, 138:1817-1832
Clarkson YL, Perkins EM, Cairncross CJ, Lyndon AR, Skehel PA, Jackson M. (2014) β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations. Hum Mol Genet. 23(14):3875-82
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.
Wishart TM, Rooney TM, Lamont DJ, Wright AK, Morton AJ, Jackson M, Freeman MR, Gillingwater TH. (2012) Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo. PLoS Genet. 8(8):e1002936.
Lise S, Clarkson Y, Perkins E et al. Recessive mutations in SPTBN2 implicate Beta-III spectrin in both cognitive and motor development. PLoS Genet (2012) Dec;8(12): e1003074
Gao Y, Perkins EM, Clarkson YL, Tobia S, Lyndon AR, Jackson M, Rothstein JD (2011) Beta-III spectrin is critical for development of Purkinje cell dendritic tree and spine morphogenesis. J Neuroscience 31, 16581-90
Clarkson YL, Gillespie T, Perkins EM, Lyndon AR and Jackson M (2010) Beta-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from Golgi. Hum. Mol. Genet. 19: 3634-364
Perkins EM, Clarkson YL, Sabatier N et al (2010) Loss of Beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behaviour and neuropathology of spinocerebellar ataxia type 5 in humans. J. Neurosci. 30: 4857-4867
Longhurst DM, Watanabe M, Rothstein JD and Jackson M (2006) Interaction of PDZRhoGEF with microtubule-associated protein 1 light chains: Link between microtubules, actin cytoskeleton and neuronal polarity. J. Biol. Chem. 281: 12030-12040
Jackson M, Song W, Liu M-Y, Jin L, Dykes-Hoberg M, Lin, C-LG, Bowers WJ, Federoff HJ, Sternweis PC and Rothstein JD (2001). Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410:89-93
Mandy Jackson publication list (PDF)
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