NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China.
Institute of Neuroscience, School of Basic Medical Science, Chongqing Medical University, Chongqing, China.
CNS Neurosci Ther. 2024 Sep;30(9):e70015. doi: 10.1111/cns.70015.
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.
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.
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.
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.
神经炎症和小胶质细胞激活相关的树突损伤导致自闭症谱系障碍（ASD）的发病机制。先前的研究表明颗粒蛋白前体（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 表达变化的机制尚不清楚。
为了研究 PGRN 在自闭症中的作用，我们立体定向地将重组 PGRN 注入 ASD 模型大鼠的海马体。此外，我们还通过 SORT1 敲低探索了 sortilin 可能是 PGRN 变化背后的因素。最终，我们旨在确定自闭症治疗的潜在靶点。
PGRN 可减轻炎症反应，保护神经元树突棘，并改善自闭症样行为。同时，在 ASD 患者和大鼠中均观察到 sortilin 表达升高和 PGRN 水平降低。升高的 sortilin 水平促进了 PGRN 内化到溶酶体中。值得注意的是，抑制 SORT1 表达可增加 PGRN 水平，减轻小胶质细胞激活和炎症，从而改善自闭症样行为。
综上所述，我们的研究结果强调了 ASD 大鼠大脑中 sortilin 水平升高，通过影响 PGRN 表达加剧树突损伤。PGRN 补充和 SORT1 敲低可能是 ASD 的治疗策略。
