top of page
_edited.jpg

Welcome to the Sleigh Laboratory

The Sleigh Laboratory works to understand mechanisms underlying peripheral nerve diseases, 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 principally funded by a Senior Non-Clinical Fellowship from the Medical Research Council UK.

 

We are fascinated by how mutations in widely expressed genes can cause selective peripheral nerve pathology. By improving our understanding of the molecular and cellular mechanisms underpinning this phenomenon, we aim to develop novel, targeted therapies for these devastating diseases.

Research

The fundamental question driving our research in the Sleigh Laboratory, 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 100 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 partner transfer RNAs (tRNAs), thereby priming the tRNAs for protein synthesis. To date, dominant, missense mutations in seven ARS-encoding genes (AARS1, GARS1, HARS1, MARS1SARS1, WARS1 and YARS1) 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 GARS1 and YARS1. GARS1 encodes glycyl-tRNA synthetase (GlyRS), which charges glycine, and is the first and best studied ARS gene associated with CMT (designated CMT type 2D, CMT2D). Similarly, dominantly inherited mutations in the tyrosyl-tRNA synthetase (TyrRS)-encoding YARS1 gene cause dominant intermediate CMT (DI-CMT). The housekeeping function of aminoacylation explains the widespread and constitutive expression of GARS1 and YARS1, but how do mutations that affect proteins found in all cells selectively trigger peripheral neurodegeneration?

 

Using CMT as a paradigm, we study the 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.

NMJ X.jpg
DRG 02.jpg

Techniques

We work with several different mouse and stem cell-based models of neuromuscular diseases (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:

Stuff_edited_edited_edited.jpg
Mut%2520%252BGDNF%2520Merge_edited_edited.jpg
AxoTrans Overview.gif

Anatomical Dissections

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 and iPSC Motor Neuron Cultures

Culturing of primary neurons and iPSC motor 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 developing 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 motor 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.

Our Team

Portrait Jan '24.jpg

Funded by the MRC (2024-29: Senior Non-Clinical Fellowship, 2019-24: Career Development Award), James is a Principal Research Fellow in the Department of Neuromuscular Diseases, leading a team of excellent scientists working on Charcot-Marie-Tooth disease (CMT). 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), extending his work on SMA and motor neuron biology. From 2012-14, he worked with 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.

David_edited.jpg

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.

Ellie picture.png

Ellie Rhymes

Ellie graduated with a BSc in Biomedical Sciences from the University of Southampton, then received her MSc in Dementia Neuroscience from UCL. She completed her PhD with Prof. Giampietro Schiavo, investigating the interaction between growth factor signalling and axonal transport deficits in ALS. Ellie is currently a postdoctoral scientist in the Sleigh Lab, testing gene therapies in several mouse models of CMT.

mmexport1636452292487.jpg

Qiuhan Lang

PhD Student

Qiuhan studied at Nankai University, China from 2016 to 2020 and graduated with a BSc in Biological Science. Interested in axonal transport, anatomical dissections and in vivo imaging, she is now pursuing a PhD in the Sleigh Lab focusing on the axonal transport of mitochondria in CMT.

Sijiang Liu

Sijiang graduated with a BSc in Pharmaceutical Science from China Medical University and Queen’s University of Belfast, then received his MRes in Biosciences from UCL. He is pursuing a PhD in the Sleigh Lab focussing on the analysis and treatment of a new mouse model for hereditary SORD neuropathy.

Louisa.jpg
Louisa Snape

Louisa graduated with a BA and then MPhil from the University of Cambridge, focusing during her Master’s degree on autophagy and ferroptosis in zebrafish models of human neurodegenerative disease. She is now pursuing her PhD on the UCL Wellcome Optical Biology program and has joined the Sleigh and Schiavo labs at the IoN as a rotation PhD student.

Lab Alumni

Ji.JPG

Ji Qu

MSc Student
2022-23

After graduating from the University of Melbourne with a B-BMED Bachelor of Biomedicine (Neuroscience), Ji gained her MSc in Clinical Neuroscience at UCL IoN working in the Sleigh Lab on the motor and sensory nervous systems of mice modelling genetic neuropathy. Ji moved on to pursue a PhD at the University of Oxford in the laboratory of Ana Domingos.

Siddhya.jpg

Siddhya Madhur

MSc Student
2022-23

Siddhya graduated from Newcastle University with a BSc (Hons) in Biomedical Sciences, and followed this by pursuing an MSc in Clinical Neuroscience in the Sleigh Lab, where she wrote a systematic review on the neuromuscular junction in CMT.

image0_edited.jpg

Undergraduate Intern
2023

As an undergraduate at Florida State University, Cassie joined the Sleigh Lab for a summer internship to learn laboratory techniques for studying neuropathology in mouse models of CMT. Back in the United States, Cassie also contributes to a Space Medicine Research group looking to understand physiological effects of space flight. After completing her BSc in Behavioral Neuroscience, she plans to continue her academic studies and earn a MSc Degree in Neuromuscular Disease at UCL to prepare her for a career as a Medical Doctor in the United States.

Marta.jpg

PhD Student (Visiting Fellow)
2023

During her PhD at the University of Milan, Marta joined the Sleigh Lab for four months as an EMBO Scientific Exchange Fellow. Interested in the pathogenetic mechanisms involved in KIF5A-related neurodegeneration, Marta joined us to assess the impact of disease-associated KIF5A mutations on axonal transport.

Screenshot 2022-01-24 at 18.56.44.png

Léa Cohen

MSc Student
2021-22

Léa completed her MSc research project in the Sleigh Lab, where she assessed the effectiveness of a novel gene therapy in mice modelling amyotrophic lateral sclerosis. As part of the Dual Master in Brain and Mind Sciences, she is now doing a second year of Master at Sorbonne Université in Paris.

Rebecca.png

Rebecca Simkin

MRes Student
2020-21

Rebecca completed her Translational Neuroscience MRes project in the Sleigh Lab, where she characterised the sensory neuron phenotypes of two different mouse models of CMT. She has continued her studies in the Department of Neuromuscular Diseases at UCL IoN, starting a position as a PhD student in the Fratta Lab. Her current project involves investigating the motor neuron response to axonal damage in mouse models of amyotrophic lateral sclerosis.

image.png

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.jpg

MRes Student
2019-20

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.jpg

Aleksandra Mech

MSc Student
2018-19

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.

Yuxin.jpg

Undergraduate Student
2018

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.

Layout 1.jpg

Publications

Pre-Prints

Vargas JNS*#, Brown AL*, Sun K, Hagemann C, Geary B, Villarroel-Campos D, Bryce-Smith S, Zanovello M, Lombardo M, Ryandov E, Stepic A, Meysman L, Majewski E, Tosolini AP, Secrier M, Kneuss MJ, Serio A, Sleigh JN, Fratta P, Schiavo G# (2023) BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration. bioRxiv

Tosolini AP#, Abatecola F, Negro S, Sleigh JN, Schiavo G# (2024) The node of Ranvier influences in vivo axonal transport of mitochondria and signalling endosomes. bioRxiv.

Publications
 

2024

Surana S#, Villarroel-Campos D, Rhymes ER, Kalyukina M, Panzi C, Novoselov SS, Fabris F, Richter S, Pirazzini M, Zanotti G, Sleigh JN, Schiavo G# (2024) The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex. EMBO J (in press).

Sleigh JN*, Mattedi F*, Richter S*, Annuario E*, Ng K, Steinmark IE, Ivanova I, Darabán IL, Joshi PP, Rhymes ER, Awale S, Yahioglu G, Mitchell JC, Suhling K, Schiavo G, Vagnoni A# (2024) Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons. Aging Cell (in press).

Rhymes ER*, Simkin RL*, Qu J, Villarroel-Campos D, Surana S, Tong Y, Qu J, Shapiro R, Burgess RW, Yang XL, Schiavo G, Sleigh JN#. Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy. Neurobiol Dis 195: 106501.

Villarroel-Campos D, Sleigh JN# (2024) Targeting muscle to treat Charcot-Marie-Tooth disease. Neural Regen Res 19: 1653-1654.

2023

Pocratsky AM#, Sleigh JN# (2023) Intraperitoneal injection of neonatal mice. Bio Protoc 13: e4826.

Sleigh JN#, Christie-Brown V, Ryburn L, Yáñez-Muñoz R (2023) Spinal muscular atrophy: A rare but treatable disease of the nervous system. Front Young Minds 11: 1023423. ​

Sleigh JN#, Villarroel-Campos D, Surana S, Wickenden T, Tong Y, Simkin RL, Vargas JNS, Rhymes ER, Tosolini AP, West SJ, Zhang Q, Yang XL, Schiavo G# (2023) Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice. JCI Insight 8: e157191.

Lang Q, Schiavo G, Sleigh JN# (2023) In vivo imaging of axonal transport in peripheral nerves of rodent forelimbs. Neuronal Signal 7: NS20220098.

Sleigh JN#, Schiavo G (2023) Neuroscience highlights in 2022: cytoskeletal transport. Lancet Neurol 22: 25-27.

2022

 

Negro S, Lauria F, Stazi M, Tebaldi T, D’Este G, Pirazzini P, Megighian A, Lessi F, Mazzanti CM, Sales G, Romualdi C, Fillo S, Lista F, Sleigh JN, Tosolini AP, Schiavo G, Viero G, Rigoni M# (2022) Hydrogen peroxide induced by nerve injury promotes axon regeneration via connective tissue growth factor. Acta Neuropathol Commun 10: 189.

Sleigh JN# (2022) Editorial: Peripheral nerve anatomy in health and disease. J Anat 241: 1083-1088.

Tosolini AP#, Sleigh JN, Surana S, Rhymes ER, Cahalan SD, Schiavo G# (2022) BDNF-dependent modulation of axonal transport is selectively impaired in ALS. Acta Neuropathol Commun 10: 121.

Sahoo PK#, Willis DE#, Sleigh JN# (2022) Editorial: Pathways and Processes Underpinning Axonal Biology and Pathobiology. Front Mol Neurosci 15: 883244.

Vargas JNS, Sleigh JN, Schiavo G# (2022) Coupling axonal mRNA transport and local translation to organelle maintenance and function. Curr Opin Cell Biol 74: 97-103.

Rossor AM#, Kapoor M, Wellington H, Spaulding EL, Sleigh JN, Burgess RW, Laurá M, Zetterberg H, Bacha A, Wu X, Heslegrave A, Shy ME, Reilly MM (2022) A longitudinal and cross-sectional study of plasma neurofilament light chain concentration in Charcot-Marie-Tooth disease. J Peripher Nerv Syst 27: 50-57.

Villarroel-Campos D, Schiavo G, Sleigh JN# (2022) Dissection, in vivo imaging and analysis of the mouse epitrochleoanconeus muscle. J Anat 241: 1108-1119.

2021

 

Tosolini AP#, Villarroel-Campos D, Schiavo G, Sleigh JN# (2021) Expanding the toolkit for in vivo imaging of axonal transport. J Vis Exp 178: e63471.

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.

2020

 

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.

2019

 

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.

(#Corresponding, *equal contribution)

Most of the above articles are freely available, but if you don't have access, please feel free to contact us to ask for a copy.

Transport Tweet 1.gif

Join Us

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:

 

 

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:

Visiting researchers We welcome researchers interested in learning techniques. Possible sources of funding include:

Contact Us

Our lab is part of the Department of Neuromuscular Diseases at the UCL Queen Square Institute of Neurology. We are located on the 5th floor of Queen Square House in Queen Square.


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,

Queen Square,

London WC1N 3BG.

+44(0)20 3448 4112

  • Twitter
  • LinkedIn
%252376%2520Serial%2520DRG_Multi_1-3_edited_edited.jpg
NMJs with mitochondria in cyan
dorsal root ganglia
vasculature of the TVA muscle
neuromuscular junctions
dorsal root ganglion
spinal cord section
signalling endosome transport in DRG neuron
neuromuscular junctions
soleus muscle section
Neuromuscular junctions and blood vessels
neuromuscular junctions (TVA musle)
bottom of page