Limits...
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.

Show MeSH

Related in: MedlinePlus

Toxic α-synuclein oligomers in relation to the pathway of amyloid fibril formation. Toxic oligomers have been reported by different studies as being “on-pathway” or “off-pathway” to amyloid fibril formation. Covalent bonding by oxidative modifications may be involved in stabilizing toxic “off-pathway” oligomers. Non-toxic oligomers that are “off-pathway” are stabilized by pharmacological inhibitors of fibril formation, such as baicalein. Toxicity of oligomers is likely to be related to their high levels of β-sheet secondary structure. Additionally, it has been hypothesized that protofibril/fibril elongation may be toxic. Blue circles- Little or no β-structure; Red circles- High β-structure.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496673&req=5

biomolecules-05-00282-f003: Toxic α-synuclein oligomers in relation to the pathway of amyloid fibril formation. Toxic oligomers have been reported by different studies as being “on-pathway” or “off-pathway” to amyloid fibril formation. Covalent bonding by oxidative modifications may be involved in stabilizing toxic “off-pathway” oligomers. Non-toxic oligomers that are “off-pathway” are stabilized by pharmacological inhibitors of fibril formation, such as baicalein. Toxicity of oligomers is likely to be related to their high levels of β-sheet secondary structure. Additionally, it has been hypothesized that protofibril/fibril elongation may be toxic. Blue circles- Little or no β-structure; Red circles- High β-structure.

Mentions: No similar study has been performed on α-synuclein, but the potential implication is that toxic oligomers of α-synuclein are “on pathway” to fibril formation. A compelling case for the importance of the fibril-forming pathway was made by enhancing α-synuclein fibrillization in vivo using genetic manipulation. Wildtype α-synuclein with a fused CL1 peptide tag was overexpressed in cell culture. The CL1 tag strongly promoted its fibrillization and cellular toxicity, which could be prevented by co-expression of the chaperone HSP70. In vivo, the toxicity of aggregating α-synuclein was confirmed by stereotaxic injection of the construct into the substantia nigra of mice. CL1-tagged α-synuclein significantly enhanced degeneration of mouse dopaminergic neurons, compared with untagged α-synuclein, and enhanced formation of LB-like inclusions [106]. However, the idea that toxicity is exclusive to “on pathway oligomers” is not widely supported by studies using recombinant protein, and differs with the methods of oligomer generation. On the one hand, several groups have confirmed the toxicity of “on pathway” oligomers, generated by lyophilization and resuspension, or incubated in the presence of iron/copper [48,54,56]. On the other hand, “off pathway” toxic oligomers were characterized by Lorenzen and co-workers, generated by stirring [47]. Toxic dopamine-modified oligomers also inhibit fibrillization [107]. Clearly, both “on pathway” and “off pathway” α-synuclein oligomers can partake in extracellular toxicity, but it remains to be seen whether “off pathway” α-synuclein oligomers are generated significantly in vivo. Figure 3 illustrates the relationship between toxic oligomers and the fibril-forming pathway.


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

Roberts HL, Brown DR - Biomolecules (2015)

Toxic α-synuclein oligomers in relation to the pathway of amyloid fibril formation. Toxic oligomers have been reported by different studies as being “on-pathway” or “off-pathway” to amyloid fibril formation. Covalent bonding by oxidative modifications may be involved in stabilizing toxic “off-pathway” oligomers. Non-toxic oligomers that are “off-pathway” are stabilized by pharmacological inhibitors of fibril formation, such as baicalein. Toxicity of oligomers is likely to be related to their high levels of β-sheet secondary structure. Additionally, it has been hypothesized that protofibril/fibril elongation may be toxic. Blue circles- Little or no β-structure; Red circles- High β-structure.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00282-f003: Toxic α-synuclein oligomers in relation to the pathway of amyloid fibril formation. Toxic oligomers have been reported by different studies as being “on-pathway” or “off-pathway” to amyloid fibril formation. Covalent bonding by oxidative modifications may be involved in stabilizing toxic “off-pathway” oligomers. Non-toxic oligomers that are “off-pathway” are stabilized by pharmacological inhibitors of fibril formation, such as baicalein. Toxicity of oligomers is likely to be related to their high levels of β-sheet secondary structure. Additionally, it has been hypothesized that protofibril/fibril elongation may be toxic. Blue circles- Little or no β-structure; Red circles- High β-structure.
Mentions: No similar study has been performed on α-synuclein, but the potential implication is that toxic oligomers of α-synuclein are “on pathway” to fibril formation. A compelling case for the importance of the fibril-forming pathway was made by enhancing α-synuclein fibrillization in vivo using genetic manipulation. Wildtype α-synuclein with a fused CL1 peptide tag was overexpressed in cell culture. The CL1 tag strongly promoted its fibrillization and cellular toxicity, which could be prevented by co-expression of the chaperone HSP70. In vivo, the toxicity of aggregating α-synuclein was confirmed by stereotaxic injection of the construct into the substantia nigra of mice. CL1-tagged α-synuclein significantly enhanced degeneration of mouse dopaminergic neurons, compared with untagged α-synuclein, and enhanced formation of LB-like inclusions [106]. However, the idea that toxicity is exclusive to “on pathway oligomers” is not widely supported by studies using recombinant protein, and differs with the methods of oligomer generation. On the one hand, several groups have confirmed the toxicity of “on pathway” oligomers, generated by lyophilization and resuspension, or incubated in the presence of iron/copper [48,54,56]. On the other hand, “off pathway” toxic oligomers were characterized by Lorenzen and co-workers, generated by stirring [47]. Toxic dopamine-modified oligomers also inhibit fibrillization [107]. Clearly, both “on pathway” and “off pathway” α-synuclein oligomers can partake in extracellular toxicity, but it remains to be seen whether “off pathway” α-synuclein oligomers are generated significantly in vivo. Figure 3 illustrates the relationship between toxic oligomers and the fibril-forming pathway.

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