Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases

Igor F. Tsigelny, Leslie Crews, Paula Desplats, Gideon M. Shaked, Yuriy Sharikov, Hideya Mizuno, Brian Spencer, Edward Rockenstein, Margarita Trejo, Oleksandr Platoshyn, Jason Yuan, Eliezer Masliah

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid β protein (Aβ) oligomers has been identified as one of the central toxic events in AD, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Aβ promotes α-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. Methodology/Principal Findings: In order to understand the molecular mechanisms involved in potential Aβ/α-syn interactions, immunoblot, molecular modeling, and in vitro studies with α-syn and Aβ were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Aβ and α-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Aβ binds α-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Aβ and the N-terminus and C-terminus of α-syn. Interacting α-syn and Aβ dimers that dock on the membrane incorporated additional α-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Aβ interacted with α-syn, forming hybrid pore-like oligomers. Moreover, cells expressing α-syn and treated with Aβ displayed increased current amplitudes and calcium influx consistent with the formation of cation channels. Conclusion/Significance: These results support the contention that Aβ directly interacts with α-syn and stabilized the formation of hybrid nanopores that alter neuronal activity and might contribute to the mechanisms of neurodegeneration in AD and PD. The broader implications of such hybrid interactions might be important to the pathogenesis of other disorders of protein misfolding.

Original languageEnglish (US)
Article numbere3135
JournalPLoS One
Volume3
Issue number9
DOIs
StatePublished - Sep 4 2008
Externally publishedYes

Fingerprint

Parkinson disease
Alzheimer disease
Oligomers
Parkinson Disease
Alzheimer Disease
pathogenesis
Synucleins
Poisons
neurodegenerative diseases
Neurodegenerative Diseases
Proteostasis Deficiencies
proteins
Nanopores
Serum Amyloid A Protein
Lewy Body Disease
amyloid
Molecular modeling
in vitro studies
Transgenic Mice
Cations

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., ... Masliah, E. (2008). Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One, 3(9), [e3135]. https://doi.org/10.1371/journal.pone.0003135

Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. / Tsigelny, Igor F.; Crews, Leslie; Desplats, Paula; Shaked, Gideon M.; Sharikov, Yuriy; Mizuno, Hideya; Spencer, Brian; Rockenstein, Edward; Trejo, Margarita; Platoshyn, Oleksandr; Yuan, Jason; Masliah, Eliezer.

In: PLoS One, Vol. 3, No. 9, e3135, 04.09.2008.

Research output: Contribution to journalArticle

Tsigelny, IF, Crews, L, Desplats, P, Shaked, GM, Sharikov, Y, Mizuno, H, Spencer, B, Rockenstein, E, Trejo, M, Platoshyn, O, Yuan, J & Masliah, E 2008, 'Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases', PLoS One, vol. 3, no. 9, e3135. https://doi.org/10.1371/journal.pone.0003135
Tsigelny, Igor F. ; Crews, Leslie ; Desplats, Paula ; Shaked, Gideon M. ; Sharikov, Yuriy ; Mizuno, Hideya ; Spencer, Brian ; Rockenstein, Edward ; Trejo, Margarita ; Platoshyn, Oleksandr ; Yuan, Jason ; Masliah, Eliezer. / Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. In: PLoS One. 2008 ; Vol. 3, No. 9.
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