Open AccessAdaptive cellular response of the substantia nigra dopaminergic neurons upon age‐dependent iron accumulation
Author(s) -
Kwon Kujin,
Cho Hwapyeong,
Lee Soyeon,
Cho Eun Jeong,
Yu Weonjin,
Kok Catherine Yen Li,
Je Hyunsoo Shawn,
Kim JaeIck,
Cho Hyung Joon,
Kwon Taejoon
Publication year - 2022
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13694
Subject(s) - substantia nigra , oxidative stress , biology , transcriptome , neuromelanin , dopaminergic , microbiology and biotechnology , downregulation and upregulation , reactive oxygen species , endocrinology , medicine , dopamine , gene expression , biochemistry , gene
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.