4 YEAR PhD IN NEUROSCIENCE
Institute of Neurology
The Graham Watts Laboratories for Research into Motor Neuron Disease
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. 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 projects are based upon the research interests of the laboratory and are designed in discussion with individual students. Specific projects currently underway in the laboratory include: the role of the heat shock response in motoneuron survival; the role of non-neuronal cells in ALS pathogenesis; axonal transport defects and motor neuron disease; mitochondrial dysfunction in models of motor neuron disease; the role of the muscle in ALS; pathogenesis of spinal bulbar muscular atrophy (SBMA) or Kennedy’s Disease, an inherited lower motoneuron degenerative disorder associated with partial androgen insensitivity, caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene.
L G Bilsland, JRT Dick, G Pryce, S. Petrosino, V Di Marzo, D Baker & L Greensmith (2006)
The neuroprotective effects of cannabinoids in the SOD1G93A mouse model of ALS.
FASEB Journal 20, 1003-1005
B Kalmar, D Kieran and L Greensmith (2005)
Molecular chaperones as therapeutic targets in amyotrophic lateral sclerosis.
Biochemical Society Transactions 33, 551-552
N. Nirmalananthan & L. Greensmith (2005)
Amyotrophic Lateral Sclerosis – Recent advances and future
Current Opinion in Neurology 18, 712-719
DM Kieran, M Hafezparast, S Bohnert, JRT Dick, G Schaivo, J Martin, E Fisher & L Greensmith (2005)
Mutations in Dynein delay disease progression in SOD1(G93A) transgenic mice, a model of ALS.
Journal of Cell Biology 169, 561-567
D Kieran, B Kalmar, JRT Dick, J Riddoch-Contreras, G Burnstock & L Greensmith (2004)
Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.
Nature Medicine 10, 402-405