The Chaperone-Like Activity of α-Synuclein Attenuates Aggregation of Its Alternatively Spliced Isoform, 112-Synuclein In Vitro: Plausible Cross-Talk between Isoforms in Protein Aggregation

• Published in: PloS one Vol. 9; no. 6; p. e98657
• Main Authors: Manda, Krishna Madhuri, Yedlapudi, Deepthi, Korukonda, Srikanth, Bojja, Sreedhar, Kalivendi, Shasi V.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.06.2014; Public Library of Science (PLoS)
• Subjects: Abnormalities; Agglomeration; Aggregates; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Alternative splicing; Alternative Splicing - genetics; Alternative Splicing - physiology; Alzheimer's disease; Amino acids; Basal ganglia; Biology; Biology and Life Sciences; Brain; C-Terminus; Central nervous system diseases; Dopamine; Enzymes; Fibrillation; Fibrils; Heat; Humans; Incubation; Isoforms; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Nitrogen dioxide; Oligomerization; Parkinson's disease; Pathogenesis; Plasmids; Polyamines; Protein interaction; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Relative abundance; Research and Analysis Methods; Rodents; Synuclein; Synucleins - chemistry; Synucleins - metabolism; Temperature; Time dependence; Transcription; United States > US; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098657

Abnormal oligomerization and aggregation of α-synuclein (α-syn/WT-syn) has been shown to be a precipitating factor in the pathophysiology of Parkinson's disease (PD). Earlier observations on the induced-alternative splicing of α-syn by Parkinsonism mimetics as well as identification of region specific abnormalities in the transcript levels of 112-synuclein (112-syn) in diseased subjects underscores the role of 112-syn in the pathophysiology of PD. In the present study, we sought to identify the aggregation potential of 112-syn in the presence or absence of WT-syn to predict its plausible role in protein aggregation events. Results demonstrate that unlike WT-syn, lack of 28 aa in the C-terminus results in the loss of chaperone-like activity with a concomitant gain in vulnerability to heat-induced aggregation and time-dependent fibrillation. The effects were dose and time-dependent and a significant aggregation of 112-syn was evident at as low as 45 °C following 10 min of incubation. The heat-induced aggregates were found to be ill-defined structures and weakly positive towards Thioflavin-T (ThT) staining as compared to clearly distinguishable ThT positive extended fibrils resulting upon 24 h of incubation at 37 °C. Further, the chaperone-like activity of WT-syn significantly attenuated heat-induced aggregation of 112-syn in a dose and time-dependent manner. On contrary, WT-syn synergistically enhanced fibrillation of 112-syn. Overall, the present findings highlight a plausible cross-talk between isoforms of α-syn and the relative abundance of these isoforms may dictate the nature and fate of protein aggregates.