Gillingwater, Tom

Parson, Simon

Horsburgh, Karen

Comley, Laura Helen

Biotechnology and Biological Sciences Research Council (BBSRC)

2012-04-27T13:38:24Z

2012-04-27T13:38:24Z

2011-11-25

Lower motor neurons of the peripheral nervous system are responsible for innervating skeletal muscle and controlling all voluntary movements of the body. Degeneration of motor neurons underlies conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors that influence the form and function of the peripheral nervous system in vivo will be important for our understanding of the neuromuscular system in health and disease. Here, I have studied the effects of three different genes and their respective protein products on the peripheral nervous system: yellow fluorescent protein (YFP), apolipoprotein E (apoE) and Ercc1 (excision repair cross-complementing group 1). YFP has been used as a reporter protein in many fields of research, including as a powerful tool for visualising neurons in mice. It is used under the assumption that it is biologically inert. However, my findings have revealed that YFP expressed in neurons in mice is not inert: it induces a cell stress response at both the RNA and the protein level and alters the time course of dying-back neuropathy. ApoE is a lipid transport protein with three distinct isoforms in humans (apoE2, apoE3 and apoE4), which are known to differentially affect risk and outcome in a number of central nervous system disorders. However, the effects of different apoE isoforms on the peripheral nervous system have yet to be established. I have shown that apoE4 delays peripheral nerve regeneration and subsequent neuromuscular junction reinnervation compared to apoE3, in the absence of any effects on normal form or function, degeneration or developmental plasticity. Ercc1 protein is involved in several DNA repair systems. Ercc1Δ/- mice have reduced levels of functional Ercc1 protein, which leads to a reduced life span and motor abnormalities, potentially due to a build of up DNA damage. Here I have shown that Ercc1Δ/- mice also have increased abnormalities at the neuromuscular junction (an early pathological target in neurodegeneration) with age. These findings contribute significantly to our understanding of the influence of specific genes on the form and function of the peripheral nervous system in health and disease.

http://hdl.handle.net/1842/5909

en

The University of Edinburgh

Mutsaers CA, Wishart TM, Lamont DJ, Riessland M, Schreml J, Comley LH, Murray LM, Parson SH, Lochmüller H, Wirth B, Talbot K, and Gillingwater TH. (2011) Reversible molecular pathology of skeletal muscle in spinal muscular atrophy. Hum Mol Genet. Epub ahead of print.

Comley LH, Fuller HR, Wishart TM, Mutsaers CA, Thomson D, Wright AK, Ribchester RR, Morris GE, Parson SH, Horsburgh K and Gillingwater TH. (2011) ApoE isoform-specific regulation of regeneration in the peripheral nervous system. Hum Mol Genet. 20(12):2406-21.

Comley LH, Wishart TM, Baxter B, Murray LM, Nimmo A, Thomson D, Parson SH and Gillingwater TH. (2011) Induction of cell stress in neurons from transgenic mice expressing yellow fluorescent protein: implications for neurodegeneration research. PLoS One. 6(3):e17639.

Murray LM, Comley LH, Gillingwater TH and Parson SH. (2011) The response of neuromuscular junctions to injury is developmentally regulated. FASEB J. 25(4):1306-13.

de Waard MC, van der Pluijm I, Zuiderveen Borgesius N, Comley LH, Haasdijk ED, Rijksen Y, Ridwan Y, Zondag G, Hoeijmakers JH, Elgersma Y, Gillingwater TH and Jaarsma D. (2010) Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol. 120(4):461-75.

Murray LM, Comley LH, Thomson D, Parkinson N, Talbot K and Gillingwater TH. (2008) Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum Mol Genet. 17(7):949-62.

peripheral nervous system

neuromuscular junction

neurodegeneration

Genetic factors influencing the peripheral nervous system in health and disease

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy