p62 accumulation and aggregation as a target for diagnostics and intervention in age-related neurodegenerative disease

The inhibition of intracellular catabolic pathway autophagy is considered to be a feature of most age-related neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease and other forms of dementia. This inhibition results in the formation of intracellular ubiquitylated aggregates containing an autophagic substrate called sequestosome-1 or p62. Accumulating p62 has detrimental effect and is both a disease biomarker and a potential target for drug interventions. Our preliminary experiments have identified a conceptually novel mechanism leading to oligomerisation and aggregation of p62. The project will investigate molecular details of this mechanism, the role it plays in the protein’s function and pathology.