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Prof Linda Greensmith

Research Summary

Our work is aimed at improving our understanding of the mechanisms involved in motoneuron death, with particular reference to the loss of motoneurons that occurs in motor neuron diseases such as Amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder in which motoneurons in the spinal cord and brain progressively die, resulting in muscle paralysis and death, usually within 2-5 years of diagnosis. There is currently no cure or treatment for this disease and so the development of an effective therapy remains an imperative. In addition, we are beginning to examine other disorders of the motor system, such as peripheral neuropathies including distal hereditary motor neuropathy, in which motoneurons are specifically affected.

ALS is a multi-factorial disorder in which different pathological mechanisms play a role. In our group we have been investigating the contribution that some of these different mechanisms make to disease including the role of protein chaperones, axonal transport defects as well as mitochondrial deficits. We hope that a greater understanding of the causative factors involved in the death of motor neurons may help us to identify new therapeutic targets.

We use a multidisciplinary approach in our experiments, examining motor neurons both in animal models of motor neuron disease as well as in primary cell cultures of motor neurons, muscles and glial cells. We also use a wide range of techniques from cellular and molecular biology to whole animal systems physiology. This combination of techniques allows us to examine the molecular and cellular changes that take place within motor neurons in culture under different conditions, to examine the effects and mechanisms of action of potential neuroprotective agents, before moving on to test the validity of our findings in vivo using animal models of motor neuron disease. The overall aim of our research program is to help in the development of effective therapeutic strategies for use in the treatment of these fatal neurodegenerative disorders.

Research Activities

  • Motor Neuron and Neuromuscular Disorders
  • Neuromuscular and Neurodegenerative Disorders
  • Neuronal chaperones and proteasomal sorting in Motor Neuron Disease
  • Protein biomarker
  • The neurogenetics of neurodegenerative disease
  • motor neuron disease
  • peripheral nerve disease especially inherited neuropathies but also inflammatory neuropathies

Recent Publications

Displaying 50 most recent publications. For the full list please visit UCL Discovery

  1. Mitchell JC,McGoldrick P,Vance C,Hortobagyi T,Sreedharan J,Rogelj B,Tudor EL,Smith BN,Klasen C,Miller CC,Cooper JD,Greensmith L,Shaw CE (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol, 125(2), 273 - 288. 10.1007/s00401-012-1043-z.
  2. Oates EC,Rossor AM,Hafezparast M,Gonzalez M,Speziani F,Macarthur DG,Lek M,Cottenie E,Scoto M,Foley AR,Hurles M,Houlden H,Greensmith L,Auer-Grumbach M,Pieber TR,Strom TM,Schule R,Herrmann DN,Sowden JE,Acsadi G,Menezes MP,Clarke NF,Züchner S,UK10K ,Muntoni F,North KN,Reilly MM (2013) Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia. Am J Hum Genet. 10.1016/j.ajhg.2013.04.018.
  3. Malik B,Nirmalananthan N,Gray AL,La Spada AR,Hanna MG,Greensmith L (2013) Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy. Brain, 136(Pt 3), 926 - 943. 10.1093/brain/aws343.
  4. McGoldrick P,Joyce P,Fisher EMC,Greensmith L (2013) Rodent models of amyotrophic lateral sclerosis Biochimica et Biophysica Acta: international journal of biochemistry and biophysics.
  5. Crul T,Toth N,Piotto S,Literati-Nagy P,Tory K,Haldimann P,Kalmar B,Greensmith L,Torok Z,Balogh G,Gombos I,Campana F,Concilio S,Gallyas F,Nagy G,Berente Z,Gungor B,Peter M,Glatz A,Hunya A,Literati-Nagy Z,Vigh L,Hoogstra-Berends F,Heeres A,Kuipers I,Loen L,Seerden JP,Zhang D,Meijering RA,Henning RH,Brundel BJ,Kampinga HH,Koranyi L,Szilvassy Z,Mandl J,Sumegi B,Febbraio MA,Horvath I,Hooper PL,Vigh L (2013) Hydroximic acid derivatives: pleiotropic hsp co-inducers restoring homeostasis and robustness. Curr Pharm Des, 19(3), 309 - 346.
  6. Rossor AM,Kalmar B,Greensmith L,Reilly MM (2012) The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry, 83(1), 6 - 14. 10.1136/jnnp-2011-300952.
  7. Rossor AM,Davidson G,Houlden HH,Kalmar B,Greensmith L,Reilly MM (2012) A novel p.glu175x premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2 NEUROMUSCULAR DISORDERS, 22, S21 - S21.
  8. Gray A,Nirmalananthan N,Malik B,Dick J,Hanna M,Greensmith L (2012) Targeting the endogenous stress response in a mouse model of SBMA NEUROMUSCULAR DISORDERS, 22, S12 - S12.
  9. Rossor A,Kalmar B,Gray A,Mustill W,Schiavo G,Cheetham ME,Reilly MM,Greensmith L,Novoselov S (2012) AN IN-VITRO STUDY OF DISTAL HEREDITARY MOTOR NEUROPATHY DUE TO HOMOZYGOUS HSJ1 MUTATIONS JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 83(3). 10.1136/jnnp-2011-301993.209.
  10. Lu CH,Petzold A,Kalmar B,Dick J,Malaspina A,Greensmith L (2012) Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS. PLoS One, 7(7), e40998. 10.1371/journal.pone.0040998.
  11. Kalmar B,Edet-Amana E,Greensmith L (2012) Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Amyotroph Lateral Scler, 13(4), 378 - 392. 10.3109/17482968.2012.660953.
  12. Ahmed M,Miller A,Hanna MG,Greensmith L (2012) Investigating the effects of pharmacological up-regulation of the heat shock response in an in-vitro model of sporadic inclusion body myositis NEUROMUSCULAR DISORDERS, 22, S26 - S26.
  13. Miller A,Ahmed M,Hanna MG,Greensmith L (2012) DEVELOPING NEW THERAPEUTIC STRATEGIES FOR INCLUSION BODY MYOSITIS JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 83(3). 10.1136/jnnp-2011-301993.140.
  14. Wade A,Thomas C,Kalmar B,Terenzio M,Garin J,Greensmith L,Schiavo G (2012) Activated leukocyte cell adhesion molecule modulates neurotrophin signaling. J Neurochem, 121(4), 575 - 586. 10.1111/j.1471-4159.2012.07658.x.
  15. Smith AS,Passey S,Greensmith L,Mudera V,Lewis MP (2012) Characterization and optimization of a simple, repeatable system for the long term in vitro culture of aligned myotubes in 3D. J Cell Biochem, 113(3), 1044 - 1053. 10.1002/jcb.23437.
  16. Wang Y,He J,McVey A,Pasnoor M,Gallagher P,Herbelin L,Statland J,Miller A,Greensmith L,Machado P,Hanna M,Barohn R,Dimachkie M (2012) Twelve-Month Change of IBMFRS in the Arimocolomol Inclusion Body Myositis Pilot Study NEUROLOGY, 78.
  17. Bryson JB,Hobbs C,Parsons MJ,Bosch KD,Pandraud A,Walsh FS,Doherty P,Greensmith L (2012) Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Hum Mol Genet, 21(17), 3871 - 3882. 10.1093/hmg/dds215.
  18. Rossor AM,Davidson GL,Blake J,Polke JM,Murphy SM,Houlden H,Innes A,Kalmar B,Greensmith L,Reilly MM (2012) A novel p.Glu175X premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2. J Peripher Nerv Syst, 17(2), 201 - 205. 10.1111/j.1529-8027.2012.00400.x.
  19. Fratta P,Malik B,Gray A,La Spada A,Hanna MG,Fisher EMC,Greensmith L (2012) FUS is not dysregulated by the spinal bulbar muscular atrophy androgen receptor polyglutamine repeat expansion Neurobiology of Aging.
  20. Jessen KR,Arthur-Farraj, PJ ,Latouche, M ,Wilton, DK ,Quintes, S ,Chabrol, E ,Banerjee, A ,Woodhoo, A ,Jenkins, B ,Rahman, M ,Turmaine, M ,Wicher, GK ,Mitter, R ,Greensmith, L ,Behrens, A ,Raivich, G ,Mirsky, R (2012) c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration Neuron, 75(4), 633 - 647. 10.1016/j.neuron.2012.06.021.
  21. McGoldrick P,Joyce P,Acevedo-Arozena A,Fisher E,Greensmith L (2012) Investigating new mutant models of MND NEUROMUSCULAR DISORDERS, 22, S13 - S13.
  22. Ahmed M,Miller A,Hanna MG,Greensmith L (2011) Investigating the effects of pharmacological up-regulation of the heat shock response on protein degradation pathways in an in-vitro model of sporadic inclusion body myositis NEUROMUSCULAR DISORDERS, 21, S26 - S27.
  23. Gray A,Malik B,Montague K,Dick J,Hanna MG,Greensmith L (2011) Investigating pathophysiology and therapeutic strategies in a mouse model of spinal and bulbar muscular atrophy (SBMA) NEUROMUSCULAR DISORDERS, 21, S10 - S10.
  24. Acevedo-Arozena A,Kalmar B,Essa S,Ricketts T,Joyce P,Kent R,Rowe C,Parker A,Gray A,Hafezparast M,Thorpe JR,Greensmith L,Fisher EM (2011) A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Dis Model Mech, 4(5), 686 - 700. 10.1242/dmm.007237.
  25. Banks GT,Haas MA,Line S,Shepherd HL,Alqatari M,Stewart S,Rishal I,Philpott A,Kalmar B,Kuta A,Groves M,Parkinson N,Acevedo-Arozena A,Brandner S,Bannerman D,Greensmith L,Hafezparast M,Koltzenburg M,Deacon R,Fainzilber M,Fisher EM (2011) Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse. J Neurosci, 31(14), 5483 - 5494. 10.1523/JNEUROSCI.5244-10.2011.
  26. Malik B,Nirmalananthan N,Bilsland LG,La Spada AR,Hanna MG,Schiavo G,Gallo JM,Greensmith L (2011) Absence of disturbed axonal transport in spinal and bulbar muscular atrophy. Hum Mol Genet, 20(9), 1776 - 1786. 10.1093/hmg/ddr061.
  27. Rossor AM,Kalmar B,Cheetham M,Schiavo G,Reilly MM,Greensmith L (2011) AN IN-VITRO STUDY OF DISTAL HEREDITARY MOTOR NEUROPATHY DUE TO HOMOZYGOUS HSJ1 MUTATIONS JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 16, S119 - S120.
  28. Kalmar B,Innes A,Rossor AM,Houlden H,Schiavo G,Reilly MM,Greensmith L (2011) ASSESSMENT OF FUNCTIONAL IMPAIRMENTS IN CELLULAR MODELS OF MUTANT HSPB1 INDUCED NEUROPATHIES JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 16, S62 - S63.
  29. Miller A,Ahmed M,Hanna MG,Greensmith L (2011) The effects of arimoclomol on pathological outcome measures of inclusion body myositis in vitro NEUROMUSCULAR DISORDERS, 21, S27 - S27.
  30. Machado P,Miller A,Parton M,Dewar L,Holton JL,Dimachkie M,Herbelir L,Greensmith L,Barohn R,Hanna MG (2011) A randomised, double-blinded, placebo-controlled pilot study assessing the safety and tolerability of Arimoclomol in sporadic inclusion body myositis (IBM) NEUROMUSCULAR DISORDERS, 21, S27 - S27.
  31. Innes A,Kalmar B,Houlden H,Reilly MM,Greensmith L (2011) Characterisation of novel mutations within heat shock protein 27 causing motor axonopathies NEUROMUSCULAR DISORDERS, 21, S3 - S3.
  32. Lu CH,Kalmar B,Malaspina A,Greensmith L,Petzold A (2011) A method to solubilise protein aggregates for immunoassay quantification which overcomes the neurofilament "hook" effect. J Neurosci Methods, 195(2), 143 - 150. 10.1016/j.jneumeth.2010.11.026.
  33. Boërio D,Greensmith L,Bostock H (2011) A model of mouse motor nerve excitability and the effects of polarizing currents. J Peripher Nerv Syst, 16(4), 322 - 333. 10.1111/j.1529-8027.2011.00364.x.
  34. Lu C,Malaspina A,Orrell R,Kalmar B,Petzold A,Greensmith L (2010) PLASMA NEUROFILAMENT HEAVY CHAIN LEVELS AS A DISEASE BIOMARKER IN THE SOD1 MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 81(11), E62 - E62. 10.1136/jnnp.2010.226340.179.
  35. Lu C,Malaspina A,Orrell R,Kalmar B,Petzold A,Greensmith L (2010) PONM06 Plasma neurofilament heavy chain levels as a disease biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry, 81(11), e62. 10.1136/jnnp.2010.226340.179.
  36. Innes A,Kalmar B,Houlden H,Reilly MM,Greensmith L (2010) Characterisation of novel mutations within HSP27 causing Charcot-Marie-Tooth disease 2F and distal hereditary motor neuropathy II NEUROMUSCULAR DISORDERS, 20, S21 - S22.
  37. Ludolph AC,Bendotti C,Blaugrund E,Chio A,Greensmith L,Loeffler JP,Mead R,Niessen HG,Petri S,Pradat PF,Robberecht W,Ruegg M,Schwalenstöcker B,Stiller D,van den Berg L,Vieira F,von Horsten S (2010) Guidelines for preclinical animal research in ALS/MND: A consensus meeting. Amyotroph Lateral Scler, 11(1-2), 38 - 45. 10.3109/17482960903545334.
  38. Boërio D,Kalmar B,Greensmith L,Bostock H (2010) Excitability properties of mouse motor axons in the mutant SOD1(G93A) model of amyotrophic lateral sclerosis. Muscle Nerve, 41(6), 774 - 784. 10.1002/mus.21579.
  39. Lu C,Petzold A,Kalmar B,Orrell R,Malaspina A,Greensmith L (2010) Plasma neurofilament heavy chain levels as a disease biomarker in SOD1 mice., SW336.
  40. Miller A,Ahmed M,Hanna MG,Greensmith L (2010) PONM17 Augmentation of the heat shock response in an in vitro model of sporadic inclusion body myositis. J Neurol Neurosurg Psychiatry, 81(11), e64. 10.1136/jnnp.2010.226340.190.
  41. Stevens JC,Chia R,Hendriks WT,Bros-Facer V,van Minnen J,Martin JE,Jackson GS,Greensmith L,Schiavo G,Fisher EM (2010) Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag--implications for research into amyotrophic lateral sclerosis (ALS). PLoS One, 5(3), e9541. 10.1371/journal.pone.0009541.
  42. El-Kadi AM,Bros-Facer V,Deng W,Philpott A,Stoddart E,Banks G,Jackson GS,Fisher EM,Duchen MR,Greensmith L,Moore AL,Hafezparast M (2010) The legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in SOD1G93A mouse model for motor neuron disease. J Biol Chem, 285(24), 18627 - 18639. 10.1074/jbc.M110.129320.
  43. McGoldrick P,Dick J,Ricketts T,Acevedo-Arozena A,Fisher E,Greensmith L (2010) Investigating novel mutant mouse models of motor neuron disease NEUROMUSCULAR DISORDERS, 20, S13 - S13.
  44. Miller AD,Ahmed M,Hanna MG,Greensmith L (2010) Augmentation of the heat shock response in an in vitro model of sporadic inclusion body myositis NEUROMUSCULAR DISORDERS, 20, S26 - S27.
  45. Ahmed M,Miller AD,Hanna MG,Greensmith L (2010) Heat shock protein induction as a therapeutic strategy for inclusion body myositis NEUROMUSCULAR DISORDERS, 20, S27 - S27.
  46. Wade A,Greensmith L,Schiavo G (2010) Investigating a novel role for the cell surface molecule ALCAM in neurotrophin signalling JOURNAL OF NEUROCHEMISTRY, 113, 30 - 30.
  47. Bilsland LG,Sahai E,Kelly G,Golding M,Greensmith L,Schiavo G (2010) Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A, 107(47), 20523 - 20528. 10.1073/pnas.1006869107.
  48. Kalmar B,Greensmith L (2009) Induction of heat shock proteins for protection against oxidative stress Advanced Drug Delivery Reviews, 61(4), 310 - 318. 10.1016/j.addr.2009.02.003.
  49. Stevens JC,Bros-Facer V,Hendriks W,van Minnen J,Greensmith L,Martin JE,Fisher EMC (2009) HOW DOES A DYNEIN MUTATION SLOW MOTOR NEURONE DISEASE? JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 80(11). 10.1136/jnnp.2009.191759b.
  50. Banks GT,Bros-Facer V,Williams HP,Chia R,Achilli F,Bryson JB,Greensmith L,Fisher EM (2009) Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice. PLoS One, 4(7), e6218..

Qualifications

  • 1989: Doctor of Philosophy, University College London
  • 1985: Postgraduate Diploma, Chelsea College
  • 1984: Bachelor of Science (Honours), University College London

Keywords

  • Axon degeneration
  • Axonal transport
  • Behavioural analysis
  • Cell culture
  • Charcot-Marie-Tooth disease
  • Development and Neurodegeneration of Motor Neurons
  • Electrophysiological recording techniques
  • Histology
  • Image analysis
  • Immunohistochemistry
  • Light microscopic techniques
  • Microglia
  • Mitochondria
  • Modelling
  • Morphology
  • Motor Neuron Diseases
  • Motor Neurone Disease
  • Mouse
  • Neuormuscular Diseases
  • Neurodegeneration
  • Neurodegenerative diseases
  • Neuromuscular junction
  • Neuron
  • Neuropathology
  • Neuropathy
  • Neuroscience
  • Protein aggregation
  • Protein misfolding
  • Retrograde and anterograde tracer
  • Transgenic mice