Protein aggregation and degradation in aging and disease: Role of polyubiquitination and autophagy

Neurodegenerative disorders such as Alzheimer's, Huntington's and Parkinson's disease are characterized by the deposition of polyubiquitinated protein aggregates. Recent results suggest that autophagy may have a protective effect in protein aggregation di seases. p62 and ubiquitin are well known components of inclusions associated with several human neurodegenerative diseases and we have reason to believe that these inclusions also would be positive for Alfy (Autophagy linked FYVE domain), as Alfy colocali ze strongly with ubiquitin and p62. Our recent data from Drosophila melanogaster show that ubiquitin and p62 gradually accumulate as flies age and we found that there is a close correlation between autophagic activity, ubiquitin/p62 levels, lifespan and a neurodegenerative phenotype. Flies with low autophagic activity were characterized by a neurodegenerative phenotype, decreased lifespan and more insoluble ubiquitin/p62 than same age control flies. Thus, reduced levels of autophagy and accumulation of u biquitin/p62 (and probably Alfy) might be good markers of early onset neurodegenerative disease and maybe also of other forms of proteopathies. At present there is no way to diagnose development of neurodegenerative disease at an early stage of disease or to follow disease progression. The ultimate goal for this project is to investigate whether accumulation of p62 and Alfy and/or reduced levels of autophagy can be used as markers for diagnosis of development and progression of neurodegenerative diseases. Our collaborator Dr Ai Yamamoto, Columbia University, New York, has developed inducible mouse models of Huntington's disease and has access to human cells (lymphocytes and fibroblasts) derived from patients with neurodegenerative diseases. PhD fellow Pau line Isakson is planning to visit the laboratory of Dr Yamamoto for 5 months to analyze protein and mRNA levels in mouse and human cells and compare levels in healthy versus diseased individuals.