Residue Glu83 plays a major role in negatively regulating alpha-synuclein amyloid formation.
Alpha-synuclein (alpha-syn) amyloid filaments are the major ultrastructural component of pathological inclusions that define several neurodegenerative disorders, including Parkinson disease and other disorders that are collectively termed synucleinopathies. Since the aggregation of alpha-syn is associated with the etiology of these diseases, defining the molecular elements that influence this process may have important therapeutics implication. The deletions of major portions of the hydrophobic region of alpha-syn (Delta74-79 and Delta71-82) impair the ability to form amyloid. However, mutating residue E83 to an A restored the ability of these proteins to form amyloid. Additionally supporting an inhibitory role of residue E83 on amyloid formation, mutating this residue to an A enhanced amyloid formation in the presence of small molecule inhibitors, such as dopamine and EGCG. Our data, therefore, suggest that the presence and placement of the highly charged E83 residue plays a significant inhibitory role in alpha-syn amyloid formation and these findings provide important insights in the planning of therapeutic agents that may be capable of preventing alpha-syn amyloid formation.
Waxman
Elisa A
EA
Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 125 John Morgan Building, Philadelphia, PA 19104-6084, USA.
Emmer
Kristel L
KL
Giasson
Benoit I
BI
D000682:Amyloid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D044950:Flavanones; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D018698:Glutamic Acid; C006680:baicalein; D002392:Catechin; C045651:epigallocatechin gallate; D004298:Dopamine