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Seeking a mechanism for the toxicity of oligomeric α-synuclein.

Roberts HL, Brown DR - Biomolecules (2015)

Bottom Line: In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells.Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress.Finally, methods of studying and manipulating oligomers within cells are described.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. H.L.Roberts@bath.ac.uk.

ABSTRACT
In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of "toxic oligomers": a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.

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Cellular effects of α-synuclein toxic oligomers, and potential links to oligomer properties. Inner shell: proposed properties of toxic oligomers. Middle shell: examples of molecular effects conferred by toxic oligomers. Outer shell: cellular systems disrupted by toxic oligomers. Edges of the box: pathological outcomes of neuron dysfunction. ER—endoplasmic reticulum. UPR—unfolded protein response.
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biomolecules-05-00282-f002: Cellular effects of α-synuclein toxic oligomers, and potential links to oligomer properties. Inner shell: proposed properties of toxic oligomers. Middle shell: examples of molecular effects conferred by toxic oligomers. Outer shell: cellular systems disrupted by toxic oligomers. Edges of the box: pathological outcomes of neuron dysfunction. ER—endoplasmic reticulum. UPR—unfolded protein response.

Mentions: An important question that still remains to be answered is: what are the molecular features of a toxic oligomer that confer toxicity? Research on other amyloidogenic proteins and their toxic oligomers provides some clues. Toxic and non-toxic oligomers of similar size and shape were compared for the bacterial protein HypF-N, and one of the major differences between them was their ability to bind ANS. ANS is a dye that binds tightly and non-specifically to hydrophobic patches on proteins, and revealed in this case that toxic oligomers expose more hydrophobic residues. Toxic oligomers also had a less well-packed hydrophobic core and greater structural flexibility, which allowed them to insert into membranes and create Ca2+ permeability. Non-toxic oligomers only associated loosely with membranes, and did not permeabilize them [60]. The enhanced exposure of hydrophobic surfaces could additionally mediate aberrant binding to multifunctional proteins, such as the 26S proteasome complex, or increase the formation of ROS [50,61,62]. Figure 2, at the end of this section, shows the hypothesized links between features of α-synuclein toxic oligomers and cellular effects. Evidence supporting various mechanisms of cellular toxicity by α-synuclein oligomers are discussed henceforth.


Seeking a mechanism for the toxicity of oligomeric α-synuclein.

Roberts HL, Brown DR - Biomolecules (2015)

Cellular effects of α-synuclein toxic oligomers, and potential links to oligomer properties. Inner shell: proposed properties of toxic oligomers. Middle shell: examples of molecular effects conferred by toxic oligomers. Outer shell: cellular systems disrupted by toxic oligomers. Edges of the box: pathological outcomes of neuron dysfunction. ER—endoplasmic reticulum. UPR—unfolded protein response.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496673&req=5

biomolecules-05-00282-f002: Cellular effects of α-synuclein toxic oligomers, and potential links to oligomer properties. Inner shell: proposed properties of toxic oligomers. Middle shell: examples of molecular effects conferred by toxic oligomers. Outer shell: cellular systems disrupted by toxic oligomers. Edges of the box: pathological outcomes of neuron dysfunction. ER—endoplasmic reticulum. UPR—unfolded protein response.
Mentions: An important question that still remains to be answered is: what are the molecular features of a toxic oligomer that confer toxicity? Research on other amyloidogenic proteins and their toxic oligomers provides some clues. Toxic and non-toxic oligomers of similar size and shape were compared for the bacterial protein HypF-N, and one of the major differences between them was their ability to bind ANS. ANS is a dye that binds tightly and non-specifically to hydrophobic patches on proteins, and revealed in this case that toxic oligomers expose more hydrophobic residues. Toxic oligomers also had a less well-packed hydrophobic core and greater structural flexibility, which allowed them to insert into membranes and create Ca2+ permeability. Non-toxic oligomers only associated loosely with membranes, and did not permeabilize them [60]. The enhanced exposure of hydrophobic surfaces could additionally mediate aberrant binding to multifunctional proteins, such as the 26S proteasome complex, or increase the formation of ROS [50,61,62]. Figure 2, at the end of this section, shows the hypothesized links between features of α-synuclein toxic oligomers and cellular effects. Evidence supporting various mechanisms of cellular toxicity by α-synuclein oligomers are discussed henceforth.

Bottom Line: In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells.Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress.Finally, methods of studying and manipulating oligomers within cells are described.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. H.L.Roberts@bath.ac.uk.

ABSTRACT
In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of "toxic oligomers": a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.

Show MeSH
Related in: MedlinePlus