All-trans retinoic acid (ATRA), a ligand of retinoic acid receptors, could regulate various biological processes by activating retinoic acid signals. Recent studies suggested that ATRA displays multiple neuroprotective effects and thereby alleviates the disease progression in a variety of neurological diseases. Our previous studies found that the impaired retinoic acid signal decreased ALDH1A2, an essential synthetase of ATRA, in the spinal cord of ALS mice. Here, we evaluated the neuroprotective and neurorestorative effects of ATRA in a SOD1-G93A transgenic mice model of ALS. We administrated ATRA(3 mg/kg) daily from the onset stage to the progression stage for 5 weeks. Behavioral tests showed that ATRA improved the forelimb grip strength in ALS mice and may slow the disease progression, but not the body weight. ATRA could completely reverse the impaired retinoic acid receptor alpha (RARα) signal in the spinal cord of ALS mice. This effect was accompanied by enhancing the degradation of misfolded proteins via the ubiquitin-proteasome system, regulating the oxidative stress, inhibiting the astrocyte activation, and promoting the neurotrophic signal recovery. Our findings are the first to indicate that the damaged retinoic acid signal is involved in the pathogenesis of ALS, and ATRA could induce the functional neuroprotection via repairing the damaged retinoic acid signal.

全反式维甲酸（ATRA）是维甲酸受体的配体，可以通过激活维甲酸信号来调节各种生物过程。最近的研究表明，ATRA 表现出多种神经保护作用，从而减轻了多种神经系统疾病的疾病进展。我们之前的研究发现，受损的视黄酸信号降低了 ALS 小鼠脊髓中 ATRA 的必需合成酶 ALDH1A2。在这里，我们评估了 ATRA 在 SOD1-G93A 转基因小鼠 ALS 模型中的神经保护和神经恢复作用。我们从发病阶段到进展阶段每天服用 ATRA（3 mg/kg），持续 5 周。行为测试表明，ATRA 改善了 ALS 小鼠的前肢握力，并可能减缓疾病进展，但不会减轻体重。ATRA 可以完全逆转 ALS 小鼠脊髓中受损的视黄酸受体 α (RARα) 信号。这种作用伴随着通过泛素-蛋白酶体系统增强错误折叠蛋白的降解，调节氧化应激，抑制星形胶质细胞活化，促进神经营养信号恢复。我们的研究结果首次表明受损的维甲酸信号参与了ALS的发病机制，而ATRA可以通过修复受损的维甲酸信号来诱导功能性神经保护。并促进神经营养信号恢复。我们的研究结果首次表明受损的维甲酸信号参与了ALS的发病机制，而ATRA可以通过修复受损的维甲酸信号来诱导功能性神经保护。并促进神经营养信号恢复。我们的研究结果首次表明受损的维甲酸信号参与了ALS的发病机制，而ATRA可以通过修复受损的维甲酸信号来诱导功能性神经保护。