Dr Tennore Ramesh

DVM, PhD

Department of Neuroscience

Non-Clinical Lecturer

t.ramesh@sheffield.ac.uk
+44 114 222 2246

Full contact details

Dr Tennore Ramesh
Department of Neuroscience
385a Glossop Road
Sheffield
S10 2HQ
Profile
  • Dec 2008-Present Non-Clinical Lecturer, Academic Neurology, University of Sheffield, UK.
  • 2004-2008 Founder, PALS Fund for ALS Drug Discovery, Ohio State University. Research scientist, Ohio State University, Columbus, OH
  • 2000-8/2003 Founding Scientist and Chief Scientific Officer, ALS-TDF, Newton, MA, USA
  • 1999- 2000 Scientist, Toxico and Pharmacogenomics, CuraGen Corporation, New Haven, CT, USA
  • 1998-1999 Post-Doctoral Research Fellow, Human Genetics, University of Michigan, Ann Arbor, MI, USA
  • 1996-1998 Post-Doctoral Research Fellow, Neurobiotechnology Center, Ohio State University, Columbus, OH, USA
  • 1992-1996 PhD, Microbiology and Immunology, University of Kentucky, Lexington, KY, USA
  • 1990-1992, MS, Animal Sciences, University of Kentucky, Lexington, KY
  • 1982-1988 B.V.Sc (D.V.M), Madras Veterinary College, India
Research interests

Amyotrophic lateral sclerosis/Motor neuron disease (ALS/MND) is an adult onset motoneuron degenerative disease with a lifetime risk of ~1/1000. Approximately 80% of the cases are fatal within five years of diagnosis. There is no cure and only one FDA approved therapy, Riluzole has a minor effect on the progression of the disease.

Mutations in genes such as SOD1, TDP-43, FUS, ANG, and VAPB also cause some forms of ALS although most forms of ALS is sporadic in nature. Despite the identification many genes causing ALS the exact mechanism of motor neuron toxicity is unclear, although a variety of mechanisms have been postulated.

Identifying the upstream events that result in toxicity is critical to impact the disease process. Protein misfolding and cellular inclusions are a common theme in many neurodegenerative diseases including ALS. How protein misfolding contributes to toxicity, if protein inclusions are protective or detrimental is presently unknown.

In most cases the accumulation of mutant proteins are not universally present in all cells but are restricted to specific cell types and also to specific regions in the CNS affected in the disease. Understanding the cause and mechanism of this toxic process is one of the focuses of my research. To understand disease process in this complex environment requires complex systems such as mice and more recently zebrafish.

My lab utilises the power of mice and fish to study the pathogenic processes involved in neuronal death. Many transgenic models of ALS have been developed and have given valuable insight into the cellular players involved in disease process. My lab recently developed a transgenic zebrafish model of ALS with mutation in the sod1 gene.

Transgenic sod1 zebrafish carrying mutant sod1 develop disease that is similar to that seen in mice and human. Additionally, these transgenic fish show early embryonic readout of mutant sod1 induced cellular stress response as early as 24 hours post-fertilization allowing us to study disease in these microscopic stages.

Zebrafish are tropical fishes who are optically transparent in early embryonic and larval stages. Organogenesis is complete and freely swimming larvae hatch as early as 72 hours post-fertilization, providing a powerful tool to study tissue specific changes in diseased animals. Using GFP transgenic lines, we can visualize motoneurons and other spinal neurons cells in living animals.

We can also analyze cell fate, axonal outgrowth and morphology, synapses (formation, maintenance, and activity), and motor behaviour. We can easily generate genetic mosaics to determine the autonomy of mutant sod1 and examine the cell autonomy of the mutant gene.

This will allow us to readily address what cells contribute to the disease and the effect of mutant cells on wild-type motoneurons, an area, which is still in need of investigation. We employ molecular, cell biology, behavioural and genetic techniques to unravel the toxic mechanisms involved in ALS pathogenesis.

Eventually, our goal is to test genes and drugs that can modify disease process to develop new therapies to treat ALS/MND.

Pathological changes observed in G93R os10 spinal cord and muscle

Figure 1: Pathological changes were observed in G93R os10 spinal cord and muscle. A) Electron microscopy of a spinal cord motoneuron from nTg (left) and G93R os10 (right) adult end-stage fish. Numerous vacuolated mitochondria were observed in G93R os10 motoneurons (top, 9,300 X) and were readily apparent at 68,000 X (bottom). B) Electron microscopy also revealed severe abnormalities in G93R os10 muscle (top, 6,800 X). Mitochondria in G93R os10 muscle also appeared to be affected, both in number and integrity, and cristae appeared to be reduced in number and lacked the normal organisation (bottom 68,000). 223 x 110mm (300 x 300 DPI).

Publications

Journal articles

Conference proceedings papers

  • Cooper-Knock J, Moll T, Ramesh T, Castelli L, Shaw C, Al-Chalabi A, McDermott C, Hautbergue G & Shaw P (2019) 11.30 Mutations in the glycosyltransferase domain of GLT8D1 cause ALS. Journal of Neurology Neurosurgery & Psychiatry, Vol. 90(12) (pp e10) RIS download Bibtex download
  • McGown A, Sharrack B & Ramesh T (2015) The development of a novel demyelination zebrafish model to be used for high-throughput drug screening of pro-myelinating compounds in multiple sclerosis. MULTIPLE SCLEROSIS JOURNAL, Vol. 21 (pp 431-431) RIS download Bibtex download
  • Alsomali N, Seytanoglu A, Valori C, Kim HR, Ning K, Ramesh T, Sharrack B, Wood JD & Azzouz M (2014) Deficiency in Gle1, an mRNA export mediator, inhibits Schwann cell development in the zebrafish embryo. FEBS JOURNAL, Vol. 281 (pp 771-771) RIS download Bibtex download
  • Hewamadduma C, Grierson A, Moens C, Pan L, Ma T, Ingham P, Ramesh T & Shaw P (2012) A novel alternative splicing event rescues the mutant tardbp phenotype in a zebrafish model of TDP-43 related Amyotrophic Lateral Sclerosis (ALS). NEUROLOGY, Vol. 78 RIS download Bibtex download
  • Hewamadduma C, Grierson A, Moens C, Pan L, Ma T, Ingham P, Ramesh T & Shaw P (2012) A novel alternative splicing event rescues the mutant tardbp phenotype in a zebrafish model of TDP-43 related Amyotrophic Lateral Sclerosis (ALS). NEUROLOGY, Vol. 78 RIS download Bibtex download
  • Ramesh T, McGown A, Al Mashhadi S, Redhead N, Lyon A, Bettie CE & Shaw PJ (2012) THE HEAT IS "ON" IN THE NEURONS: NEURONAL STRESS IN A SOD1 ZEBRAFISH MODEL OF MND AFFECTS NEUROMUSCULAR JUNCTION INTEGRITY AND CAUSES MUSCLE DENERVATION. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol. 83(3) RIS download Bibtex download
  • Seytanoglu A, Valori C, Ramesh T, Sharrack B & Azzouz M (2010) Reduced GLE1 Protein Levels Cause Axonal Growth Defects in Zebrafish Motor Neurons. NEUROLOGY, Vol. 74(9) (pp A441-A441) RIS download Bibtex download
Research group

Research projects available:

  • Study of early pathological events in MND using transgenic sod1 zebrafish.
  • Development of new zebrafish models of MND
  • Development of new tools for study of disease progression and drug screening in mouse model of MND

Research Group:

  • Mr. Alexander McGown: PhD student: Primary supervisor
  • Dr. Channa Hewamadduma: PhD student: Co supervisor

Alumni:

  • Natasha Redhead: BMedSci student:
  • Sufana Al Mashhadi: MSc Molecular Neuroscience
  • Marc Da Costa: PhD Student: Co supervisor
  • Sumona Dhara: MSc in Stem Cell and Regenerative Medicine
  • Fabiola Sica: MSc Molecular Neuroscience
Grants
  • Completed: ALS Association: Development of SOD1 zebrafish model of ALS: 2004-2007: Co-PI
  • ALS Association: Development of modifier screen using transgenic sod1 zebrafish: 2007:Co-PI
  • Sheffield Hospitals Charitable Trust: 2010: PI
  • Fondation Thierry Latran: 2010: PI
  • MNDA 2011
Professional activities

Items of Esteem:

  • 2003-2006 Scientific Advisory Board, Western ALS study group (WALS)
  • 1998 NIH Reproductive sciences training grant fellowship
  • 1996 NIH Neuropharmacology training grant Fellowship
  • 1995 Best Poster award, Graduate student research day
  • 1990 Graduate school Fellowship