背景:神经炎症和小胶质细胞活化相关的树突状损伤与孤独症谱系障碍(ASD)的发病机制有关。以往的研究表明,前颗粒蛋白(PGRN)是一种与炎症和突触发育相关的生长因子,但PGRN在自闭症中的作用以及PGRN表达变化的潜在机制仍不清楚.
目的:研究PGRN对自闭症的影响,我们将重组PGRN立体定向注射到ASD模型大鼠的海马中。此外,我们探讨了sortilin可能是通过利用SORT1敲低PGRN改变背后的因素的可能性。最终,我们的目标是确定治疗自闭症的潜在目标。
结果:PGRN可以减轻炎症反应,保护神经元树突棘,改善类似自闭症的行为。同时,在ASD患者和大鼠中均观察到sortilin的表达升高和PGRN的水平降低。增强的分拣素水平促进PGRN内化到溶酶体中。值得注意的是,抑制SORT1表达扩增PGRN水平,小胶质细胞活化减少,减轻炎症,从而减轻自闭症样行为。
结论:总的来说,我们的发现强调了ASD大鼠大脑中sortilin水平的升高,通过影响PGRN表达加剧树突损伤。PGRN补充和SORT1敲除具有作为ASD治疗策略的潜力。
BACKGROUND: Neuroinflammation and microglial activation-related dendritic injury contribute to the pathogenesis of Autism Spectrum Disorder (ASD). Previous studies show that Progranulin (PGRN) is a growth factor associated with inflammation and synaptic development, but the role of PGRN in autism and the mechanisms underlying changes in PGRN expression remain unclear.
OBJECTIVE: To investigate the impact of PGRN in autism, we stereotactically injected recombinant PGRN into the hippocampus of ASD model rats. Additionally, we explored the possibility that sortilin may be the factor behind the alterations in PGRN by utilizing SORT1 knockdown. Ultimately, we aimed to identify potential targets for the treatment of autism.
RESULTS: PGRN could alleviate inflammatory responses, protect neuronal dendritic spines, and ameliorate autism-like behaviors. Meanwhile, elevated expression of sortilin and decreased levels of PGRN were observed in both ASD patients and rats. Enhanced sortilin levels facilitated PGRN internalization into lysosomes. Notably, suppressing SORT1 expression amplified PGRN levels, lessened microglial activation, and mitigated inflammation, thereby alleviating autism-like behaviors.
CONCLUSIONS: Collectively, our findings highlight elevated sortilin levels in ASD rat brains, exacerbating dendrite impairment by affecting PGRN expression. PGRN supplementation and SORT1 knockdown hold potential as therapeutic strategies for ASD.