Abstract
Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein α-synuclein plays a role in the pathogenesis of PD: Fibrillar α-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in α-synuclein are linked to early-onset disease. Accordingly, the fibrillization of α-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the α-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar α-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. α-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with α-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic α-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of α-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of α-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random α-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by α-synuclein is necessary for neurodegeneration in transgenic animal models of PD.
| Original language | English |
|---|---|
| Pages (from-to) | 23-33 |
| Number of pages | 11 |
| Journal | Journal of Molecular Neuroscience |
| Volume | 23 |
| Issue number | 1-2 |
| Publication status | Published - 1 Apr 2004 |
| Externally published | Yes |
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Keywords
- Dopamine
- Fibril
- Membrane
- Parkinson's disease
- Protofibril
- Synuclein
- Yeast
ASJC Scopus subject areas
- Neuroscience(all)
- Biochemistry
- Genetics
Cite this
Interactions among α-synuclein, dopamine, and biomembranes : Some clues for understanding neurodegeneration in Parkinson's disease. / Rochet, Jean Christophe; Outeiro, Tiago Fleming; Conway, Kelly A.; Ding, Tomas T.; Volles, Michael J.; Lashuel, Hilal A.; Bieganski, Robert M.; Lindquist, Susan L.; Lansbury, Peter J.
In: Journal of Molecular Neuroscience, Vol. 23, No. 1-2, 01.04.2004, p. 23-33.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interactions among α-synuclein, dopamine, and biomembranes
T2 - Some clues for understanding neurodegeneration in Parkinson's disease
AU - Rochet, Jean Christophe
AU - Outeiro, Tiago Fleming
AU - Conway, Kelly A.
AU - Ding, Tomas T.
AU - Volles, Michael J.
AU - Lashuel, Hilal A.
AU - Bieganski, Robert M.
AU - Lindquist, Susan L.
AU - Lansbury, Peter J.
PY - 2004/4/1
Y1 - 2004/4/1
N2 - Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein α-synuclein plays a role in the pathogenesis of PD: Fibrillar α-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in α-synuclein are linked to early-onset disease. Accordingly, the fibrillization of α-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the α-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar α-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. α-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with α-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic α-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of α-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of α-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random α-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by α-synuclein is necessary for neurodegeneration in transgenic animal models of PD.
AB - Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein α-synuclein plays a role in the pathogenesis of PD: Fibrillar α-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in α-synuclein are linked to early-onset disease. Accordingly, the fibrillization of α-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the α-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar α-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. α-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with α-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic α-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of α-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of α-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random α-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by α-synuclein is necessary for neurodegeneration in transgenic animal models of PD.
KW - Dopamine
KW - Fibril
KW - Membrane
KW - Parkinson's disease
KW - Protofibril
KW - Synuclein
KW - Yeast
UR - http://www.scopus.com/inward/record.url?scp=4344641972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4344641972&partnerID=8YFLogxK
M3 - Article
C2 - 15126689
AN - SCOPUS:4344641972
VL - 23
SP - 23
EP - 33
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
SN - 0895-8696
IS - 1-2
ER -