Amy Innes Amy Innes, second year PhD student, MRC Centre for Neuromuscular Diseases I did my four-year undergraduate degree in Anatomical Sciences with Industrial Experience at Manchester University, England and Mayo Clinic, USA. After finishing my final year I went back to my industrial placement to work for a year gaining experience as a research technician. During my two years work experience, my research interests were focused on the pathology of neurodegeneration in relation to Alzheimer’s disease and Frontotemporal dementia. From this research and my degree speciality I became very interested in the field of neuromuscular diseases and felt that the new centre would be the perfect environment for me to link a passion for neuroscience and a desire to work towards a better quality of life for people with these diseases. PhD Project: Charcot-Marie-Tooth disease (CMT) is highly heterogeneous group of neuromuscular diseases which affect 1 in 2500 people. CMT2 F is a slow, progressive motor disease with only mild to moderate sensory deficits and dHMN II is a pure motor neuropathy with no signs of a sensory deficit. Recently a number of mutations have been discovered in the HSP27 gene which cause Charcot-Marie-Tooth disease 2F (CMT2F) and distal Hereditary Motor Neuropathy (dHMN II) (Houlden et al., 2008). Heat Shock Protein 27 (HSP27 / HSPB1) is a well characterised member of small heat shock proteins. HSP27 is a ubiquitous protein that has a role in normal cell maintenance as well as in conditions of cellular stress. During stress condition the expression of HSP27 can be upregulated in a number of cell types, including neurons and glial cells. HSP27 acts to rebalance cell homeostasis by facilitating protein folding, degradation, clearance and transport. In stress conditions HSP27 has multiple cytoprotective actions. For example, it stabilises cytoskeletal elements and inhibits the apoptotic cell death cascade. In neurons it also exerts more specific roles; expression of HSP27 promotes axonal growth, regeneration and protects against oxidative stress. Since the discovery of disease causing mutations in the HSP27 gene, there has been some research carried out to elucidate how these mutations can lead to CMT. There is some evidence that axonal transport is impaired but the experimental evidence for this is rather circumstantial and the exact elements of the transport machinery that is involved in the pathology is still elusive. Therefore in this project we aim to elucidate what cellular functions are affected by disease causing HSP27 mutations. Due to the wide range of vital functions performed by HSP27 in neuronal cells, it is important to carry out a systematic study of HSP27 mutations in vitro to try and elucidate the pathways and molecular mechanisms affected by dHMN II and CMT2 F. We will utilise a number of mutations that are located at different parts of the gene to possibly identify differential effects by the individual mutations. In our in vitro model system expressing each HSP27 mutation we are currently testing some of the molecular pathways possibly involved in axonal degeneration. At the end of this project we are hoping to identify clear therapeutic targets for a possible treatment strategy for this type of CMT. |
|
|
 |
||