Affiliation:
1. Department of Geriatric Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province,
650032, PR China
2. Yunnan Province Clinical Research Center for Gerontology, Kunming, Yunnan Province,
650032, PR China
3. Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province,
610000, PR China
Abstract
Background:
Parkinson’s disease (PD) is associated with coiled-coil-helix-coiled-coilhelix
domain containing 2 (CHCHD2) downregulation, which has been linked to reduced cyclocytase
activity and increased levels of oxygen free radicals, leading to mitochondrial fragmentation
and apoptosis. Little is known about how CHCHD2 normally functions in the cell and, therefore,
how its downregulation may contribute to PD.
Objective:
This study aimed to identify such target genes using chromatin immunoprecipitation
sequencing from SH-SY5Y human neuroblastoma cells treated with neurotoxin 1-methyl-4-
phenylpyridinium (MPP+) as a PD model.
Methods:
In this study, we established a MPP+ -related SH-SY5Y cell model and evaluated the
effects of CHCHD2 overexpression on cell proliferation and apoptosis. At the same time, we used
high-throughput chromatin immunoprecipitation sequencing to identify its downstream target gene
in SH-SY5Y cells. In addition, we verified the possible downstream target genes and discussed their
mechanisms.
Results:
The expression level of α-synuclein increased in SH-SY5Y cells treated with MPP+, while
the protein expression level of CHCHD2 decreased significantly, especially after 24 h of treatment.
Chip-IP results showed that CHCHD2 might regulate potential target genes such as HDX, ACP1,
RAVER2, C1orf229, RN7SL130, GNPTG, erythroid 2 Like 2 (NFE2L2), required for cell differentiation
1 homologue (RQCD1), solute carrier family 5 member 7 (SLA5A7), and NAcetyltransferase
8 Like (NAT8L). NFE2L2 and RQCD1 were validated as targets using PCR and
western blotting of immunoprecipitates, and these two genes together with SLA5A7 and NAT8L
were upregulated in SH-SY5Y cells overexpressing CHCHD2. Downregulation of CHCHD2 may
contribute to PD by leading to inadequate expression of NFE2L2 and RQCD1 as well as, potentially,
SLA5A7 and NAT8L.
Conclusion:
Our results suggest that CHCHD2 plays a protective role by maintaining mitochondrial
homeostasis and promoting proliferation in neurons. In this study, the changes of CHCHD2 and
downstream target genes such as NFE2L2/RQCD1 may have potential application prospects in the
future. These findings provide leads to explore PD pathogenesis and potential treatments.
Funder
National Natural Science Foundation of China
Yunnan Province Clinical Research Center for Neurological Diseases
Scientific Research Fund Project of Yunnan Education Department
Publisher
Bentham Science Publishers Ltd.
Subject
Cellular and Molecular Neuroscience,Developmental Neuroscience,Neurology
Cited by
1 articles.
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