Phosphatidylserine enhancesIKBKAPtranscription by activating the MAPK/ERK signaling pathway

Abstract

Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD.

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

“…Previous FD drug discoveries have mainly attempted to elevate IKAP levels [47–50]. Phosphatidylserine (PS), a food supplement with no reported side effects, elevates IKBKAP transcription in cells generated from FD patients [10,51], in a mouse model for FD [52], and in preliminary results of clinical trials in FD patients [53]. Mechanistically, PS releases cells generated from FD patients from cell cycle arrest [10].…”

“…Also, treatment with PS upregulates IKBKAP transcription by activation of the MAPK/ERK pathway, which activates the transcription factors CREB and ELK1 that bind to the IKBKAP promoter region. This in turn enhances cell mobility [51]. Chronic administration of PS to normal adult rats promotes cell survival as shown by a significant increase in BrdU-positive proliferating cells [54], a reduction in pro-inflammatory signals [55], and inactivation of JNK and p38 signals after lipopolysaccharide treatment [56].…”

Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells

“…Many of the small-molecule drugs that have been shown to improve IKBKAP exon 20 splicing, have broad non-specific effects on mRNA splicing or transcription (15–17,19). These drugs therefore pose the risk of off-target effects.…”

“…Recently, another drug, RECTAS, was shown to improve splicing of IKBKAP (18) and also EGCG has a positive effect on IKBKAP exon 20 splicing (9). Phosphatidylserine treatment affects the MAPK/ERK signaling pathway resulting in increased transcription of IKBKAP (19). Overall, the effect of these treatments is not specific to IKBKAP , and a treatment of FD, which specifically targets IKBKAP exon 20 splicing is thus highly desirable to avoid potential off-target effects.…”

Sensing mechanisms and individuality of heat stress in mammalian cells

“…It has been shown recently by Zhou and coworkers that PS maintains the lateral segregation of Ras nanoclustering and therefore a potential mediator for a lipid mediated signaling (Zhou et al 2014;Zhou and Hancock 2015). In addition to that, treating human fibroblasts by PS resulted in an increased ERK 1/2 signaling which is known to be activated through Ras (Donyo et al 2016). On the otherhand JNK can be actviated through the activation of small GTPases with increasing PS on the plasma membrane as well (Figure 3.8) (Han et al 2001;Kay and Grinstein 2013).…”