Protein Degradation in Neurodegeneration: The Ubiquitin Pathway

The distinguishing feature of idiopathic chronic neurodegenerative disease is its relationship to age. Even in familial disease, clinical symptoms emerge in later life. The diseases are associated with intraneuronal misfolded proteins. This implies that age-related problems in proteostasis are central to disease progression. Proteostasis is the synthesis and degradation of proteins. There is little evidence for abnormal protein synthesis in sporadic neurodegenerative disease. The two major systems of protein degradation in the cell are the ubiquitin proteasome system and autophagy. Both systems are controlled by protein ubiquitylation. The diseases are characterized by the accumulation of ubiquitylated protein aggregates, implying that the ubiquitin proteasome system or autophagy is malfunctioning or overwhelmed. Kinase-and ubiquitin-dependent systems exist to detect abnormal proteins in the cell. A full characterization of these enzymes in the recognition and disposal of abnormal proteins will lead to a fuller understanding of the diseases and to the development of novel therapeutic interventions. © 2011 International Society of Neuropathology.