Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α-synuclein (α-syn) in the central nervous system. Aggregation of α-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore-like structures are unclear. We utilized computer modeling and cell-based studies to investigate the process of oligomerization of wild-type and A53T mutant α-syn in membranes. The studies suggest that α-syn penetrates the membrane rapidly, changing its conformation from α-helical towards a coiled structure. This penetration facilitates the incorporation of additional α-syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild-type α-syn. After 4 ns of simulation of the protein-membrane model, α-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular α-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant α-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) α-syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of α-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.
Parkinson 's disease ( PD ) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α - synuclein ( α - syn ) in the central nervous system . Aggregation of α - syn into oligomers with a ring - like appearance has been proposed to play a role in toxicity . However , the molecular mechanisms and the potential sequence of events involved in the formation of pore - like structures are unclear . We utilized computer modeling and cell - based studies to investigate the process of oligomerization of wild - type and A53 T mutant α - syn in membranes . The studies suggest that α - syn penetrates the membrane rapidly , changing its conformation from α - helical towards a coiled structure . This penetration facilitates the incorporation of additional α - syn monomers in the complex , and the subsequent displacement of phospholipids and the formation of oligomers in the membrane . This process occurred more rapidly , and with a more favorable energy of interaction , for mutant A53 T compared with wild - type α - syn . After 4 ns of simulation of the protein - membrane model , α - syn had penetrated through two - thirds of the membrane . By 9 ns , the penetration of the annular α - syn oligomers can result in the formation of pore - like structures that fully perforate the lipid bilayer . Experimental incubation of recombinant α - syn in synthetic membranes resulted in the formation of similar pore - like complexes . Moreover , mutant ( A53 T ) α - syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures , resulting in greater neuronal permeability , as demonstrated with the calcein efflux assay . These studies provide a sequential molecular explanation for the process of α - syn oligomerization in the membrane , and support the role of formation of pore - like structures in the pathogenesis of the neurodegenerative process in PD .
Which disease of the central nervous system is characterized by the presence of Lewy bodies?
Which disease of the central nervous system is characterized by the presence of Lewy bodies ?
Parkinson's disease (PD)
Parkinson's disease (PD)