Modulation of human α-synuclein aggregation by a combined effect of calcium and dopamine

Manish Kumar Jain, Rajiv Bhat

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Parkinson's disease is characterized by the deposition of aggregated α-syn and its familial mutants into Lewy bodies leading to death of dopaminergic neurons. α-syn is involved in Ca(II) and dopamine (DA) signaling and their adequate balance inside neuronal cytoplasm is essential for maintaining healthy dopaminergic neurons. We have probed the binding energetics of Ca(II) and DA to human α-syn and its familial mutants A30P, A53T and E46K using isothermal titration calorimetry and have investigated the conformational and aggregation aspects using circular dichroism and fluorescence spectroscopy. While binding of Ca(II) to α-syn and its familial mutants was observed to be endothermic in nature, interaction of DA with α-syn was not detectable. Ca(II) enhanced fibrillation of α-syn and its familial mutants while DA promoted the formation of oligomers. However, Ca(II) and DA together critically favored the formation of protofibrils that are more cytotoxic than the mature fibrils. Using fluorescently labeled cysteine mutant A90C, we have shown that different aggregating species of α-syn formed in the presence of Ca(II) and DA are internalized into the human neuroblastoma cells with different rates and are responsible for the differential cytotoxicity depending on their nature. The findings put together suggest that an interplay between the concentrations of Ca(II), DA and α-syn can critically regulate the formation of various aggregating species responsible for the survival of dopaminergic neurons. Modulating this balance leading to either complete suppression of α-syn aggregation or promoting the formation of mature fibrils could be used as a strategy for the development of drugs to cure Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)115-128
Number of pages14
JournalNeurobiology of Disease
Volume63
DOIs
StatePublished - Mar 2014

Keywords

  • Amyloid
  • Calcium
  • Cytotoxicity
  • Dopamine
  • EGCG
  • Human α-syn

ASJC Scopus subject areas

  • Neurology

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