Paper Citing NAMD - Abstract
Tsigelny, Igor F.; Crews, Leslie; Desplats, Paula; Shaked, Gideon M.; Sharikov, Yuriy; Mizuno, Hideya; Spencer, Brian; Rockenstein, Edward; Trejo, Margarita; Platoshyn, Oleksandr; Yuan, Jason X. -J.; Masliah, Eliezer
Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases
PLOS ONE, 3 Art. No. e3135, SEP 4 2008
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 beta protein (A beta) oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that A beta promotes alpha-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 A beta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and A beta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, A beta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that A beta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ringlike pentamers. Interactions occurred between the N-terminus of A beta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and A beta dimers that dock on the membrane incorporated additional alpha-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, A beta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with A beta displayed increased current amplitudes and calcium influx consistent with the formation of cation channels. Conclusion/Significance: These results support the contention that A beta directly interacts with alpha-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.
