Journal
ONCOTARGET
Volume 7, Issue 7, Pages 7441-7454Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7046
Keywords
aging; hemoglobin; alpha-synuclein; mitochondrion; Parkinson's disease; Gerotarget
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Funding
- Natural Science Foundation of China [81371200, 81071014, 81401042]
- National Science and Technology Support Program [2012BAI10B03]
- Special Scientific Research Funds for Capital Health Development [2011-1001-01]
- National Basic Research (973) Program of China [2011CB504101]
- Natural Science Foundation of Beijing [7122035]
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Neuronal hemoglobin (nHb) plays a critical role in maintaining normal mitochondrial functioning in the brain. However, in aging and Parkinson's disease (PD) brains, mitochondrial nHb levels are greatly reduced in neurons that accumulate a-synuclein (alpha-syn), suggesting a link between the two proteins. In this study, we demonstrate that alpha-syn and Hb can form a complex in both brain tissue and peripheral red blood cells (RBCs) in aging cynomolgus monkeys. nHb-alpha-syn complex levels in the mitochondrial fraction of the striatum decreased with age; this was negatively correlated with levels in the cytoplasmic fraction and in RBCs and was accompanied by a reduction in mitochondrial free nHb. In contrast, no changes in nHb-alpha-syn complex formation or free nHb levels were detected in the cerebellum. In vitro studies using a cultured dopaminergic cell line showed that intracellular accumulation of alpha-syn caused an elevation in nHb-alpha-syn complex levels in both mitochondrial and cytoplasmic fractions as well as a reduction in mitochondrial free nHb. nHb overexpression increased free nHb levels in mitochondria, stabilized mitochondrial membrane potential, and reduced alpha-syn-induced apoptosis. The above results suggest that alpha-syn forms a complex with nHb in selected regions of the aging brain, thereby decreasing mitochondrial function and increasing the risk of PD.
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