alpha-synuclein and Disease

Oligomeric forms of amyloid aggregates have been detected in the brains and tissues of patients suffering from neurodegenerative disorders such as Parkinson's disease, and it is widely thought that such species are key pathogenic agents in the development and spreading of the disease; however, the study of these species has been proven to be extremely challenging, primarily as a result of their intrinsically transient nature and high levels of heterogeneity. Identifying the structural nature and the details of the mechanisms of formation and interconversion of individual oligomeric species, particularly those with high toxicity, is of fundamental importance not only for understanding the mechanisms of protein misfolding and amyloid aggregation but also for the identification of diagnostic and therapeutic targets. In this review, we will focus on the current knowledge of the multitude of oligomeric forms of α-synuclein that have been reported to date, with particular emphasis on their structural features and possible relationship to other amyloid species, in order to build a clearer understanding of the types of oligomeric species that accumulate during the aggregation of α-synuclein and to develop a comprehensive picture of the misfolding behavior of the protein.

Topics: alpha-Synuclein; Amino Acid Sequence; Amyloid; Disease; Humans; Models, Molecular; Protein Multimerization

The covalent attachment of small ubiquition-like modifier (SUMO) polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are many proteins implicated in human diseases including cancer and Huntington's, Alzheimer's, and Parkinson's diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. The results of two more recent studies identify two additional human disease-associated proteins that are sumoylated, amyloid precursor protein (APP), and lamin A. APP sumoylation modulates Aβ peptide levels, suggesting a potential role in Alzheimer's disease, and decreased lamin A sumoylation due to mutations near its SUMO site has been implicated in causing some forms of familial dilated cardiomyopathy.

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Animals; Ataxin-1; Ataxins; Disease; Humans; Huntingtin Protein; Intracellular Signaling Peptides and Proteins; Neoplasms; Nerve Tissue Proteins; Neurodegenerative Diseases; Nuclear Proteins; Oncogene Proteins; Protein Deglycase DJ-1; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Superoxide Dismutase; Superoxide Dismutase-1; tau Proteins