title: Effects of intravenous immunoglobulin on alpha synuclein aggregation and neurotoxicity.
abstract: α-Synuclein is thought to contribute to the pathogenesis of Parkinson's disease (PD). It is the main protein in Lewy bodies, the pathognomonic inclusion bodies in the PD substantia nigra, and mutations which increase its aggregation and/or expression are associated with familial early-onset parkinsonism. Soluble oligomers are considered to be α-synuclein's most neurotoxic conformation. We previously reported that intravenous immunoglobulin (IVIG) products contain specific antibodies to α-synuclein which do not prevent development of four-day α-synuclein oligomers. The objective of this study was to further examine IVIG's effects on α-synuclein's aggregation and neurotoxicity. The IVIG product Gammagard (Baxter Healthcare) did not prevent the development of nine-day α-synuclein oligomers, nor did it degrade preformed oligomers, as shown by western blots performed on gels run under reducing/denaturing conditions and native gels. In western blots of native gels, an additional low molecular weight band (~22 kDa) was detected in α-synuclein incubated for four days in Gammagard, but not in Gammagard alone. No significant differences were found for Thioflavin-T reactivity between α-synuclein amorphous aggregates grown in Gammagard vs. those grown in phosphate-buffered saline. Gammagard partially protected SK-N-BE(2)M17 human neuroblastoma cells against α-synuclein oligomer toxicity (p = 0.007 vs. protective effects of normal human IgG). These findings suggest that although IVIG does not prevent α-synuclein aggregation, it still may reduce α-synuclein neurotoxicity through an unknown mechanism.
authors.affiliation: Department of Neurology Research, William Beaumont Hospital Research Institute, 3811 West Thirteen Mile Road, Royal Oak, MI 48073, USA. Lynnae.Smith@beaumont.edu
authors.forename: Lynnae M
authors.initials: LM
authors.lastname: Smith
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Klaver
authors.forename: Mary P
authors.initials: MP
authors.lastname: Coffey
authors.forename: Loan
authors.initials: L
authors.lastname: Dang
authors.forename: David A
authors.initials: DA
authors.lastname: Loeffler
mesh_terms: D052160:Benzothiazoles; D045744:Cell Line, Tumor; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D011485:Protein Binding; D011487:Protein Conformation; D013844:Thiazoles; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D016756:Immunoglobulins, Intravenous; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T