LncRNA MALAT1 targeting miR‐124‐3p regulates DAPK1 expression contributes to cell apoptosis in Parkinson's Disease

Abstract

Death associated protein kinase 1 (DAPK1) was initially discovered in the progress of gamma-interferon induced programmed cell death, it is a key factor in the central nervous system, including Parkinson's disease (PD). However, the underlying mechanisms of DAPK1 in PD remain unclear and this research work aims to explore the potential mechanisms of DAPK1 in PD. In the study, we exposed SH-SY5Y cells to MPP + and treated mice with MPTP to investigate the roles of DAPK1 in PD and the underlying mechanisms. The results indicated that the expression of DAPK1 is significantly upregulated and negatively correlated with miR-124-3p levels in SH-SY5Y cells treated by MPP + , and miR-124-3p mimics could effectively inhibit DAPK1 expressions and alleviate MPP +-induced cell apoptosis. In addition, knockdown MALAT1 reduces the levels of DAPK1 and the ratio of SH-SY5Y cell apoptosis, which is reversed via miR-124-3p inhibitor in vitro. Similarly, knockdown MALAT1 could improve behavioral changes and reduce apoptosis by miR-124-3p upregulation and DAPK1 downregulation in MPTP induced PD mice. Taken together, our data showed that lncRNA MALAT1 positively regulates DAPK1 expression by targeting miR-124-3p, and mediates cell apoptosis and motor disorders in PD. In summary, these results suggest that MALAT1/miR-124-3p /DAPK1 signaling cascade mediates cell apoptosis in vitro and in vivo, which may provide experimental evidence of developing potential therapeutic strategies for PD.

Role of Long Noncoding RNAs in Parkinson’s Disease: Putative Biomarkers and Therapeutic Targets

“…lncRNA MALAT1 is highly expressed in PD as a ceRNA to regulate miRNA expression. e knockout of MALAT1 in mice inhibited the MPTPinduced apoptosis of dopaminergic neurons by upregulating miR-124 [31,34]. MALAT1/miR-205-5p axis regulates MPP(+)-induced apoptosis by targeting LRRK2 [33].…”

Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease

“…LncRNA-p21 was shown to regulate the MPP-induced neuronal injury in SH-SY5Y cells via the miR-626-TRMP2 regulatory network [77]. MALAT1 acts as a mediator of cell apoptosis in PD mice and cellular models [129,130]. Further, the downregulation of lncRNA BACE1-AS in a PD rat model was reported to reduce the production of nitric oxide synthase, and thus, prevent oxidative stress [131].…”

“…Not only small ncRNAs but also long ncRNAs appear to be involved in brain-heart interactions. Indeed, a recent study showed that the lncRNA MALAT1 is a positive regulator of apoptosis and acts by inhibiting miR-124 levels in SH-SY5Y neuronal cell line and mice PD model [130]. MALAT1 is also known as a positive regulator of cardiomyocyte apoptosis and cardiac fibrosis [184,185].…”

“… Role of lncRNAs in Parkinson’s disease [ 77 , 86 , 91 , 116 , 118 , 127 , 128 , 129 , 130 , 131 , 132 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ]. …”

Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease

“…Further data showed that HOTAIR was upregulated in PD mouse model and improved the stability of LRRK2 mRNA by enhancing its expression and thus promoting the apoptosis of dopaminergic neurons [ 126 ]. Recently, it was also reported that the inhibition of lncRNA MALAT1 in PD mice induced the apoptosis of DA neurons by upregulating miR-124 [ 59 , 60 ]. Several studies have explored the potential of lncRNAs as attractive diagnostic and prognostic factors in neurodegenerative disease [ 127 ].…”