Molecular profiling of differentially vulnerable synaptic populations and in-vivo phenotypic assessment identifies regulators of neuronal stability

1. The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
2. Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK
3. Keele University, Institute for Science and Technology in Medicine, Keele, UK
4. Department of Neuroscience, Institute of Psychiatry, King’s College London, London SE5 9NU, UK
5. Centre for Integrative Physiology, University of Edinburgh, EH9 8XD, UK
6. Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK
7. Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, CA 90502,USA

Synapses are an early pathological target in a wide range of neurodegenerative conditions including well-known adult onset Alzheimer’s, Parkinson’s and Huntington’s disease [1-3] and diseases of childhood such as the motor neurone disease - Spinal Muscular Atrophy and the neuronal ceroid lipofuscinoses (NCLs; A.K.A Batten disease) [4-6]. However, our understanding of the mechanisms regulating the stability of synapses and their exceptional vulnerability to neurodegenerative stimuli remains in its infancy.

To address this we are using the NCLs as a tool to identify novel regulators of synaptic stability, contributing to our understanding of a broad range of diseases and highlighting novel therapeutic targets. The NCLs, are the most frequent autosomal-recessive disease of childhood [7]. There are currently 14 individual genes which mutations are capable of affecting lysosomal function, all of which result in similar phenotype including blindness, cognitive/motor deficits, seizures and premature death. Mutations in CLN3 underlie a juvenile form of NCL (JNCL or CLN3 disease), the most prevalent variant worldwide [8]. Differential vulnerability of distinct synaptic populations across different brain regions has been described in other models of NCL variants [5, 6] but not yet in JNCL.

Here, we describe the synaptic loss pattern in the Cln3 null mouse model of JNCL (Cln3-/-). Secondly, we use this differential pattern of synaptic loss to map molecular expression profiles across three brain regions. Thirdly, this region vulnerability expression mapping revealed conserved molecular alterations between JNCL and other neurodegenerative conditions [9]. Finally, we demonstrate that genetic and/or pharmacological manipulation of candidate expression in Drosophila is sufficient to modulate disease progression in-vivo.

References

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3. Murphy KP et al. Neurosci, 2000
4. Murray LM et al. Hum Mol Genet, 2008.
5. Kielar C et al. Hum Mol Genet, 2009.
6. Partanen S et al. J. Neuropathol. Exp. Neurol., 2008
7. Goebel, HH, J. Child. Neurol, 1995
8. Palmer DN. et al. Biochim Biophys Acta, 2013
9. Wishart TM et al. PLoS Genet, 2012

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* entered into the PhD student poster competition