Regulation of RAGE splicing by hnRNP A1 and Tra2β‐1 and its potential role in AD pathogenesis

Abstract

The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, full-length membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis, either via interaction of mRAGE with β-amyloid peptide (Aβ) or inhibition of the mRAGE-activated signaling pathway. In the present study, we showed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and Transformer2β-1 (Tra2β-1) were involved in the alternative splicing of mRAGE and esRAGE. Functionally, two factors had an antagonistic effect on the regulation. Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1. Moreover, the ratios of mRAGE/esRAGE and hnRNP A1/Tra2β-1 were increased in peripheral blood mononuclear cells from AD patients. The results provide a molecular basis for altered splicing of mRAGE and esRAGE in AD pathogenesis. The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis. Mechanism for imbalanced expression of these two isoforms in AD brain remains elusive. We proposed here a hypothetic model to illustrate that impaired glucose metabolism in AD brain may increase the expression of splicing protein hnRNP A1 and reduce Tra2β-1, which cause the imbalanced expression of mRAGE and esRAGE.

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

“…In support of this notion, TRA2␤ is reduced in the liver and skeletal muscle of obese, IGT-T2DM individuals (29,35). In the present study, we found lower concentrations of esRAGE in obese individuals compared with lean.…”

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

“…In addition, impaired mitochondrial complex I activity, which is well-documented in PD, reduces the availability of the NAD + co-factor required for the activities of various ALDH isoforms in removing reactive aldehydes. The decreased functions of ALDH isozymes following exposure to environmental toxins and/or reduced ALDH expression (Song et al, 2011) are likely to play an important role in the pathophysiology of PD (Liu et al, 2015). The knockout mice deficient of Aldh1a1 and Aldh2 (Aldh1a1(−/−) ×Aldh2(−/−) genes, exhibited age-dependent deficits in motor performance on rotarod and gait analysis.…”

“…In fact, both nitroxidative stress and mitochondrial dysfunction are considered as the major contributing factors for the development and progression of many pathological conditions, including neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), alcoholic dementia, brain ischemia-reperfusion injury and traumatic brain injury (TBI) (Johri and Beal, 2012; Navarro and Boveris, 2008) (Figure 1). Many of these neurological diseases may have different etiological factors, but may share common factors of increased nitroxidative stress and mitochondrial dysfunction, likely resulting from the protein post-translational modifications (PTMs) including oxidation, nitration, hyperphosphorylation, acetylation, glycosylation and formation of various protein adducts (Abdelmegeed and Song, 2014; Byun et al, 2012, 2014; Franco et al, 2013; Liu et al, 2015; Jin et al, 2014; Narayan et al, 2015; Song et al, 2014; Sultana et al, 2013; Tepper et al, 2014; Zhang et al, 2013). …”

Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation

“…Недавно установлено, что уровень esRAGE в сыворотке крови человека может служить новым маркером для диагностики заболеваний, связан-ных с нарушением экспрессии RAGE [26]. Показано, что уровень плазменного esRAGE может маркировать тяжесть патологического состояния при хронической обструктивной болезни легких [27], диабете 1-го типа [28], болезни Альцгеймера [29,30]. Обратная зависи-мость между уровнем esRAGE и ранними изменениями в почках свидетельствует о потенциальной роли esRAGE в развитии диабетической нефропатии [28].…”

“…В недавних исследованиях показано, что в альтернативный сплайсинг mRAGE и esRAGE вовлечены гетерогенный ядерный рибонуклеопротеин А1 (hnRNP А1) и трансформер 2β-1 (Tra2β-1). Предполагается, что нарушение метаболизма глюкозы в мозге пациентов с болезнью Альцгеймера может увеличивать экспрессию белка сплайсинга hnRNP A1 и понижать экспрессию Tra2β-1, что приводит к несбалансированной экспрессии mRAGE и esRAGE [30].…”