Induction of KLF4 Contributes to the Neurotoxicity of MPP + in M17 Cells: A New Implication in Parkinson’s Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease in humans. The effect of Krüppel-like factor (KLF) 4 in PD is unknown. In this study, KLF4 was found to be increased in both a time-dependent manner and a dose-dependent manner in response to the incubation with 1-methyl-4-phenylpyridinium (MPP+) in human dopamine neuroblastoma M17 cells, suggesting a potential role in MPP + -induced neurotoxicity. Following experiments showed that overexpression of KLF4 in M17 cells promoted MPP + -induced oxidative stress, embodied by exacerbated reactive oxygen species, 4-hydroxy-2-nonenal, and protein carbonyls. Furthermore, overexpression of KLF4 slowed cell proliferation and promoted lactate dehydrogenase release. Conversely, inhibition of KLF4 in M17 cells attenuated MPP + -induced neurotoxicity. The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4. Moreover, promoter luciferase experiments showed that transcriptional activity on SOD1 was inhibited by KLF4. All the results indicated that KLF4 promoted the neurotoxicity of MPP + via inhibiting the transcription of SOD1, suggesting a potential mechanism of increased oxidative stress and cell death in Parkinson's disease.

Systematic analysis of transcription‐level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain‐specific metabolic network

“…Among those, the dysregulation of Sox2, which was also predicted as a regulator in schizophrenia, led to oxidative stress and, hence, neurodegeneration [41,42]. Krüppel‐like factor (KLF) 4, which is identified in our analysis in all the investigated diseases except Schizophrenia (Supplementary File 3), have recently been assigned a role in Parkinson's disease through oxidative stress [43].…”

“…Among those, the dysregulation of Sox2, which was also predicted as a regulator in schizophrenia, led to oxidative stress and, hence, neurodegeneration [41,42]. Krüppel-like factor (KLF) 4, which is identified in our analysis in all the investigated diseases except Schizophrenia (Supplementary File 3), have recently been assigned a role in Parkinson's disease through oxidative stress [43]. Creatine helps to supply energy to all cells in the body, and deficiencies in the creatine biosynthetic pathway lead to the malfunction of brain and various severe neurological defects [44].…”

MiR-212 Attenuates MPP+-Induced Neuronal Damage by Targeting KLF4 in SH-SY5Y Cells

“… 21 Moreover, KLF4 was demonstrated to enhance oxidative stress, block proliferation, and promote LDH release in human dopamine neuroblastoma M17 cells induced by MPP + . 27 …”

Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans

“…The most significant SNP, rs139300691 at 9q31.2, is located 336 kb upstream of the gene Kruppel-like factor 4 ( KLF4 ), a transcript factor expressed in neural stem cells with expression recently linked to increased oxidative stress and cell death in PD in vitro [42]. Additional top SNPs in AAs were mapped at or near protocadherin 10 ( PCDH10 ), transcription factor 4 ( TCF4 ), myosin VB ( MYO5B ) and CD2 .…”