TY - JOUR
T1 - Individual Amino Acid Supplementation Can Improve Energy Metabolism and Decrease ROS Production in Neuronal Cells Overexpressing Alpha-Synuclein
AU - Delic, Vedad
AU - Griffin, Jeddidiah W.D.
AU - Zivkovic, Sandra
AU - Zhang, Yumeng
AU - Phan, Tam Anh
AU - Gong, Henry
AU - Chaput, Dale
AU - Reynes, Christian
AU - Dinh, Vinh B.
AU - Cruz, Josean
AU - Cvitkovic, Eni
AU - Placides, Devon
AU - Frederic, Ernide
AU - Mirzaei, Hamed
AU - Stevens, Stanley M.
AU - Jinwal, Umesh
AU - Lee, Daniel C.
AU - Bradshaw, Patrick C.
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media, LLC.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with l-serine, l-proline, l-aspartate, or l-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or l-valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons.
AB - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with l-serine, l-proline, l-aspartate, or l-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or l-valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons.
KW - Alpha-synuclein
KW - Amino acids
KW - Citric acid cycle
KW - Iron
KW - Metabolic therapy
KW - Mitochondrial
KW - Parkinson’s disease
KW - Proteomics
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UR - http://www.scopus.com/inward/citedby.url?scp=85020527425&partnerID=8YFLogxK
U2 - 10.1007/s12017-017-8448-8
DO - 10.1007/s12017-017-8448-8
M3 - Article
C2 - 28620826
AN - SCOPUS:85020527425
SN - 1535-1084
VL - 19
SP - 322
EP - 344
JO - NeuroMolecular Medicine
JF - NeuroMolecular Medicine
IS - 2-3
ER -