Of bones and brains – the relationship between familial Paget’s disease of bone and motor neurone disease

Numerous genes have been found to be associated with susceptibility to motor neurone disease (MND) including SQSTM1, mutations in which were previously also identified in patients with the skeletal disorder Paget’s disease of bone (PDB). Coexistence of MND and PDB is apparently rare and precisely how different SQSTM1 mutations (some of which are common to both disorders) can lead to neurodegeneration or PDB is currently unknown. This project will investigate molecular defects and disease mechanisms associated with different disease-linked SQSTM1 mutations, with particular emphasis on intracellular protein degradation systems (ubiquitin-proteasome system and autophagy). Protein chemistry, cell biology and proteomic approaches will be applied to provide novel insights in to disease aetiology.