Abstract
Aberrant aggregation of α-synuclein (α-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of α-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on α-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form α-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of α-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant α-syn revealed the presence of oligomeric α-syn in nondegenerating dopaminergic neurons that do contain insoluble α-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of α-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 10068-10078 |
| Number of pages | 11 |
| Journal | Journal of Neuroscience |
| Volume | 26 |
| Issue number | 39 |
| DOIs | |
| State | Published - Sep 27 2006 |
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Keywords
- Catecholamines
- Neurodegeneration
- Parkinson's disease
- Protein aggregation
- Tyrosine hydroxylase
- α-synuclein
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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Cytosolic catechols inhibit α-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates. / Mazzulli, Joseph R.; Mishizen, Amanda J.; Giasson, Benoit I.; Lynch, David R.; Thomas, Steven A.; Nakashima, Akira; Nagatsu, Toshiharu; Ota, Akira; Ischiropoulos, Harry.
In: Journal of Neuroscience, Vol. 26, No. 39, 27.09.2006, p. 10068-10078.Research output: Contribution to journal › Article
TY - JOUR
T1 - Cytosolic catechols inhibit α-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates
AU - Mazzulli, Joseph R.
AU - Mishizen, Amanda J.
AU - Giasson, Benoit I.
AU - Lynch, David R.
AU - Thomas, Steven A.
AU - Nakashima, Akira
AU - Nagatsu, Toshiharu
AU - Ota, Akira
AU - Ischiropoulos, Harry
PY - 2006/9/27
Y1 - 2006/9/27
N2 - Aberrant aggregation of α-synuclein (α-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of α-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on α-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form α-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of α-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant α-syn revealed the presence of oligomeric α-syn in nondegenerating dopaminergic neurons that do contain insoluble α-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of α-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.
AB - Aberrant aggregation of α-synuclein (α-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of α-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on α-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form α-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of α-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant α-syn revealed the presence of oligomeric α-syn in nondegenerating dopaminergic neurons that do contain insoluble α-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of α-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.
KW - Catecholamines
KW - Neurodegeneration
KW - Parkinson's disease
KW - Protein aggregation
KW - Tyrosine hydroxylase
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=33749170166&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749170166&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0896-06.2006
DO - 10.1523/JNEUROSCI.0896-06.2006
M3 - Article
VL - 26
SP - 10068
EP - 10078
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 39
ER -