Welcome to the Sleigh Lab
The Sleigh Lab works to understand mechanisms underlying hereditary peripheral nerve conditions, such as Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Established in 2019, we are based at the UCL Queen Square Institute of Neurology and are currently principally funded by the Medical Research Council UK.
We are fascinated by how mutations in widely expressed genes can cause selective peripheral nerve pathology. We believe that by improving our understanding of the molecular and cellular mechanisms underpinning this phenomenon, we will be able to develop novel, targeted therapies for these devastating diseases.
The fundamental question driving our research in the Sleigh Lab, is ‘how do mutations in widely expressed genes cause selective peripheral nerve dysfunction and degeneration?' Mutations in many different genes required throughout the body manifest in a very specific detrimental effect on motor and sensory nerves, and we want to better understand the molecular and cellular mechanisms that cause this.
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder and is the principal focus of our research.
Caused by mutations in more than 90 different genes, CMT is a genetically diverse group of peripheral neuropathies characterised by progressive motor and sensory nerve dysfunction leading to muscle weakness and sensory impairment. The gene family linked to more subtypes of CMT than any other, encodes the aminoacyl tRNA-synthetase (ARS) enzymes, which charge specific amino acids to their cognate transfer RNAs (tRNAs), thereby priming the tRNAs for protein translation. To date, dominant, missense mutations in five ARS-encoding genes (GARS, YARS, AARS, HARS, and WARS) have been identified to cause CMT. However, whether these CMT subtypes result from the same or similar pathomechanisms remains to be resolved.
We primarily work on GARS and YARS. GARS encodes glycyl-tRNA synthetase (GlyRS), which charges glycine, and is the first and best studied ARS gene linked to CMT (designated CMT type 2D, CMT2D). Similarly, dominantly inherited mutations in the tyrosyl-tRNA synthetase (TyrRS)-encoding YARS gene cause dominant intermediate CMT (DI-CMT). The housekeeping function of aminoacylation explains the widespread and constitutive expression of GARS and YARS, but how do mutations that affect proteins found in all cells selectively trigger peripheral neurodegeneration?
Using CMT as a paradigm, the Sleigh Lab is studying causes of motor and sensory nerve deterioration and the mechanisms underpinning the dynamic cellular process of axonal transport. By improving understanding of neuropathic pathways and associated pathologies, we aim to generate pre-clinical molecular therapies for genetic peripheral nerve diseases. Additionally, by researching relatively rare conditions, we expect to make key discoveries about the cellular processes and pathways essential to neuronal homeostasis and viability.
We work with several different mouse models of neuromuscular disease (e.g. CMT and ALS) to determine the mechanisms underlying neurodegeneration. To do this, we combine a range of standard methods (e.g. western blotting, immunohistochemistry, quantitative real-time PCR) with more specialised approaches to assess motor and sensory nerve pathologies both in vitro and in vivo:
Intricate dissections of the peripheral nervous system for comparative anatomical assessments. These allow us to better understand disease pathogenesis and the impact of therapeutic intervention.
Primary Neuron Cultures
Primary culturing of motor and sensory neurons for live imaging. This allows us to track the in vitro dynamics of diverse axonal cargoes, such as signalling endosomes, mitochondria and lysosomes. We do this in mass culture, as well as in specially designed microfluidics that allow physical and fluidic separation of cell bodies from axons and growth cones.
In vivo Imaging
Live imaging of the intact mouse nervous system in vivo. We have pioneered real-time imaging of peripheral nerves in live mice, allowing us to assess the dynamics of varied cargoes (e.g. signalling endosomes and mitochondria) both in axons and at the neuromuscular junction within muscles.
In addition to this, we are beginning to develop novel, pre-clinical adeno-associated virus (AAV) therapies for neuromuscular diseases, as well as exploring the differentiation and live imaging of induced pluripotent stem cell-derived neurons.
The development of novel techniques is critical to the advancement of our understanding of the peripheral nervous system, and we are continually adapting and improving our methodologies to aid this pursuit.
James received his undergraduate Masters in Biology (MBiol) from the University of Bath (2005-09), which included a year at Harvard Medical School (2007-08) researching spinal muscular atrophy (SMA). He then completed his MRC-funded DPhil at the University of Oxford (2009-12) with Prof. Kevin Talbot, extending his work on SMA and motor neuron biology. From 2012-14, he worked in the laboratory of Dr. Zameel Cader focusing on Charcot-Marie-Tooth disease (CMT). This CMT work was further developed through a Wellcome Trust-funded Sir Henry Wellcome Postdoctoral Fellowship (2014-18), conducted at the UCL Queen Square Institute of Neurology under the mentorship of Prof. Giampietro Schiavo. Funded by a Career Development Award from the MRC (2019-24), James is now a Senior Research Fellow in the Department of Neuromuscular Diseases, leading a small team of excellent scientists.
David arrived in London in 2015 from the Strait of Magellan via Santiago. He then gained his MSc in neuromuscular diseases, followed by his PhD, working on the molecular mechanisms underlying motor neuron disease pathology. David is currently a post-doctoral scientist in the Sleigh Lab at UCL IoN, developing and testing gene therapies for Charcot-Marie-Tooth 2D.
Rebecca studied at the University of Bristol from September 2017 and graduated in July 2020 receiving a BSc (Hons) in Pharmacology. Her undergraduate laboratory project involved characterising the pharmacological properties of elinogrel, AZD-1283 and PSB-0739 using an overexpression model of the P2Y12 receptor in HEK293T cells. Currently, Rebecca is studying for an MRes in Translational Neuroscience at UCL Queen Square Institute of Neurology and has joined the Sleigh Laboratory for the research component of her studies. This exciting project focuses on exploring common pathomechanisms underlying CMT using several different neuropathy models. Rebecca discovered a range of new hobbies during lockdown including baking, HIITs with Joe Wicks and walking. Her greatest achievement this year is completing the 2020 Virtual Virgin Money London Marathon to raise funds for both VICTA and Breast Cancer Now.
Jobert completed a short postdoctoral project in the Sleigh Lab working on organelle transport in human axons. He is now in the laboratory of Prof. Giampietro Schiavo continuing his research to understand the molecular underpinnings of axonal transport. In particular, Jobert is exploring the regulation of the dynein motor complex and exactly how specific metabolic signalling pathways affect the function of dynein within axons.
Tahmina completed her MRes laboratory project in the Sleigh Lab, studying neurotrophic signalling in CMT. After her MRes, she started a PhD at the UCL Institute of Child Health investigating renal lymphatics in diabetic kidney disease. Her research focuses on trying to understand how lymphangiogenesis and associated inflammation develops in diabetic kidney disease using a novel mouse model of the condition.
Aleksandra studied the structure of the NMJ for her MSc laboratory project, and then started her PhD in Genetics of Addiction at Queen Mary University of London. She is now using genetic and developmental analyses of zebrafish to identify novel alleles and molecular mechanisms contributing to drug-seeking and impulse control - core behaviours predictive of vulnerability to drug addiction. Aleksandra is also performing human genetic analysis that will allow her to link her zebrafish findings to human studies. She hopes to be able to identify shared genetic loci affecting both addiction and hypomania.
As an undergraduate at Imperial College London, Yuxin completed a summer project in the Sleigh Lab, studying sensory pathology in mouse models of CMT and ALS. She then completed her BSc degree in 'Biology with a Year in Research' specialising in neuroscience and systems biology. For her undergraduate thesis, she studied snout morphology and feeding ecology of extant crocodilians with Dr. Arkhat Abzhanov. Shortly after graduating in 2019, Yuxin joined the laboratory of Andreas Schaefer at the Francis Crick Institute as a PhD student, where she is studying neural circuits in mouse olfactory bulb using calcium imaging and electron microscopy.
More coming soon...
Villarroel-Campos D, Schiavo G, Sleigh JN# (2021) Dissection, in vivo imaging and analysis of the mouse epitrochleoanconeus muscle. J Anat (in press).
Mejia Maza A, Jarvis S, Lee WC, Cunningham TJ, Schiavo G, Secrier M, Fratta P, Sleigh JN, Fisher EMC#, Sudre CJ# (2021) NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease. Sci Rep 11: 12251.
Sleigh JN#, Mech AM, Aktar T, Zhang Y, Schiavo G (2020) Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels. Front Cell Neurosci 14: 232.
Sleigh JN#, Mech AM, Schiavo G (2020) Developmental demands contribute to early neuromuscular degeneration in CMT2D mice. Cell Death Dis 11: 564.
Tosolini AP#, Sleigh JN# (2020) Intramuscular delivery of gene therapy for targeting the nervous system. Front Mol Neurosci 13: 129.
Sleigh JN#, West SJ, Schiavo G (2020) A video protocol for rapid dissection of mouse dorsal root ganglia from defined spinal levels. BMC Res Notes 13: 302.
Mech AM, Brown AL, Schiavo G, Sleigh JN# (2020) Morphological variability is greater at developing than mature mouse neuromuscular junctions. J Anat 237: 603-617.
Sleigh JN#, Tosolini AP#, Schiavo G# (2020) In vivo imaging of anterograde and retrograde axonal transport in rodent peripheral nerves. In: Babetto E (ed.), Axon Degeneration: Methods and Protocols. Methods Mol Biol 2143: 271–292.
Rossor AM#, Sleigh JN, Groves M, Muntoni F, Reilly MM, Hoogenraad CC, Schiavo G# (2020) Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy. Acta Neuropath Commun 8: 34.
Sleigh JN#, Tosolini AP, Gordon D, Devoy A, Fratta P, Fisher EMC, Talbot K, Schiavo G# (2020) Mice carrying ALS mutant TDP-43, but not mutant FUS, display in vivo defects in axonal transport of signalling endosomes. Cell Rep 30: 3655–3662.
Sleigh JN# (2020) Axonal transport: The delivery system keeping nerve cells alive. Front Young Minds 8: 12.
Surana S#, Villarroel-Campos D, Lazo OM, Moretto E, Tosolini AP, Rhymes ER, Richter S, Sleigh JN, Schiavo G# (2020) The evolution of the axonal transport toolkit. Traffic 21: 13–33.
Sleigh JN*, Rossor AM*, Fellows AD, Tosolini AP, Schiavo G# (2019) Axonal transport and neurological disease. Nat Rev Neurol 15: 691–703.
Williamson MG, Finelli MJ, Sleigh JN, Reddington A, Gordon D, Talbot K, Davies KE#, Oliver PL# (2019) Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo. Hum Mol Genet 28: 3584–3599.
Kalinski AL, Kar AN, Craver J, Tosolini AP, Sleigh JN, Lee SJ, Hawthorne A, Brito-Vargas P, Miller-Randolph S, Passino R, Shi L, Wong VSC, Picci C, Smith DS, Bassell GJ, Willis DE, Havton LA, Schiavo G, Giger RJ, Langley B, Twiss JL# (2019) Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. J Cell Biol 218: 1871–1890.
Spotlight: Van den Bosch (2019) HDAC6 and Miro1: Another interaction causing trouble in neurons. J Cell Biol 218: 1769-1770.
(#Corresponding, *equal contribution)
Most of the above articles are freely available, but if you cannot get access, please feel free to contact us to ask for a copy.
We are always looking for enthusiastic and motivated scientists wishing to combine live imaging with comparative anatomical techniques to understand the peripheral nervous system. Unfortunately, there are currently no positions available. Nonetheless, there is always the possibility to create opportunities, so do please contact us, if you are interested.
Postdoctoral researchers Positions will be advertised on our site when they become available. In addition, we are open to supporting applications from talented postdoctoral researchers with varied backgrounds wishing to join the laboratory. Possible funding options include:
Doctoral students We offer rotation and PhD projects to students on several UCL PhD programmes, including:
We are also open to proposals from students wishing to pursue their own, new and exciting programmes of research. The UCL Research Scholarships provide an opportunity to do this.
Masters students We offer laboratory projects to Masters students on a variety of UCL courses, for example:
Undergraduate and summer students Interested undergraduate students who wish to gain laboratory experience should contact James with a CV and brief description of scientific interests. There are several potential funding sources for placements, including:
We are also affiliated with the UK Dementia Research Institute at University College London.
Department of Neuromuscular Diseases,
UCL Queen Square Institute of Neurology,
University College London,
Rooms 511 and 528,
Queen Square House,
London WC1N 3BG.
+44(0)20 3448 4112