The Autism‐Related lncRNA MSNP1AS Regulates Moesin Protein to Influence the RhoA, Rac1, and PI3K/Akt Pathways and Regulate the Structure and Survival of Neurons

Abstract

Autism spectrum disorder (ASD) is a complex disease involving multiple genes and multiple sites, and it is closely related to environmental factors. It has been gradually revealed that long noncoding RNAs (lncRNAs) may regulate the pathogenesis of ASD at the epigenetic level. In neuronal cells, the lncRNA moesin pseudogene 1 antisense (MSNP1AS) forms a double-stranded RNA with moesin (MSN) to suppress moesin protein expression. MSNP1AS overexpression can activate the RhoA pathway and inhibit the Rac1 and PI3K/Akt pathways; however, the regulation of Rac1 by MSNP1AS is not associated with MSN, and the effect on the RhoA pathway may also be associated with other factors. MSNP1AS can decrease the number and length of neurites, inhibit neuronal cell viability and migration, and promote apoptosis. Downregulation of MSN expression functions similarly to MSNP1AS, and its overexpression can block the above functions of MSNP1AS. In addition, in vivo experiments show that MSN improves social interactions and reduces repetitive behaviors in BTBR mice, decreases the activity of RhoA and restores the activity of PI3K/Akt pathway. Therefore, the abnormal expression of MSNP1AS in ASD patients might influence the structure and survival of neuronal cells through the regulation of moesin protein expression to facilitate the development and progression of ASD. These findings provide new evidence for studying the mechanisms of lncRNAs in ASD.

Long Non-Coding RNA (lncRNA) Roles in Cell Biology, Neurodevelopment and Neurological Disorders

“…Other studies showed that a certain single nucleotide polymorphism in the antisense transcript to a processed pseudogene of moesin ( MSNP1AS ) also could be present and upregulated in some ASD cases [ 197 ]. This lncRNA regulates the expression of moesin, which is an important factor in neurons regulating the immune response and architecture of the nucleus [ 3 , 65 , 198 , 199 ]. Upregulation of MSNP1AS leads to downregulation of moesin translation, negatively affecting neurite morphology and function [ 65 , 170 , 198 , 199 ].…”

Not So Dead Genes—Retrocopies as Regulators of Their Disease-Related Progenitors and Hosts

“…It is quite common to observe coexisting diseases, such as epilepsy, depression or attention deficit hyperactivity disorder (ADHD) [ 109 ]. The development of ASD is caused by multiple factors, among which there are more than 130 genes [ 83 ]. It has been reported that some lncRNAs may also be involved in ASD pathogenesis, especially at the epigenetic level [ 117 ].…”

“…Downregulation of MSN protein expression leads to inhibited activation of the PI3K/Akt signaling pathway. MNSP1AS is one of the major factors influencing the PI3K/Akt pathway, and the RhoA and Rac1 pathways are important for neuronal structure and survival [ 83 ]. It was reported that MSNP1AS and MSN are able to form dsRNA (double stranded RNA), which suppresses the expression of the protein encoded by the parental gene [ 83 , 118 , 119 ].…”

“…MNSP1AS is one of the major factors influencing the PI3K/Akt pathway, and the RhoA and Rac1 pathways are important for neuronal structure and survival [ 83 ]. It was reported that MSNP1AS and MSN are able to form dsRNA (double stranded RNA), which suppresses the expression of the protein encoded by the parental gene [ 83 , 118 , 119 ]. Furthermore, overexpression of MSNP1AS in ASD patients has an impact on smaller amounts and lengths of neurites in human neural progenitor cell lines [ 118 , 119 ].…”

Brain Long Noncoding RNAs: Multitask Regulators of Neuronal Differentiation and Function

“…Considering the importance of lncRNAs in neuronal physiology it is not surprising that dysregulation of lncRNAs in the brain might be linked to neurodevelopmental disorders [ 160 , 161 ], autism spectrum disorders [ 162 , 163 , 164 ], substance use [ 165 ], intellectual disability [ 166 ], neurodegenerative diseases and neurological disorders [ 167 , 168 ]. A growing number of studies report that lncRNAs are associated with the pathology and development of neurodegenerative diseases [ 80 , 114 , 169 , 170 ].…”