한빛사 논문
Kujin Kwon1 | Hwapyeong Cho1 | Soyeon Lee2 | Eun Jeong Cho2 | Weonjin Yu3 | Catherine Yen Li Kok3 | Hyunsoo Shawn Je3,4 | Jae-Ick Kim2 | Hyung Joon Cho1 | Taejoon Kwon1,5
1Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea
2Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Korea
3Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore City, Singapore
4Advanced Bioimaging Center, Academia, Singapore City, Singapore
5Center for Genome Integrity, Institute for Basic Science (IBS), Ulsan, Korea
Kujin Kwon and Hwapyeong Cho contributed equally to this work.
Correspondence Hyung Joon Cho and Taejoon Kwon
Abstract
Progressive iron accumulation in the substantia nigra in the aged human brain is a major risk factor for Parkinson's disease and other neurodegenerative diseases. Heavy metals, such as iron, produce reactive oxygen species and consequently oxidative stress in cells. It is unclear, however, how neurons in the substantia nigra are protected against the age-related, excessive accumulation of iron. In this study, we examined the cellular response of the substantia nigra against age-related iron accumulation in rats of different ages. Magnetic resonance imaging confirmed the presence of iron in 6-month-old rats; in 15-month-old rats, iron accumulation significantly increased, particularly in the midbrain. Transcriptome analysis of the region, in which iron deposition was observed, revealed an increase in stress response genes in older animals. To identify the genes related to the cellular response to iron, independent of neurodevelopment, we exposed the neuroblastoma cell line SH-SY5Y to a similar quantity of iron and then analyzed their transcriptomic responses. Among various stress response pathways altered by iron overloading in the rat brain and SH-SY5Y cells, the genes associated with topologically incorrect protein responses were significantly upregulated. Knockdown of HERPUD1 and CLU in this pathway increased susceptibility to iron-induced cellular stress, thus demonstrating their roles in preventing iron overload-induced toxicity. The current study details the neuronal response to excessive iron accumulation, which is associated with age-related neurodegenerative diseases.
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