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<p>GPAM, a key enzyme for lipid synthesis, is predominantly expressed in astrocytes (ASTs), where it facilitates lipid supply for myelin formation. Our previous studies identified <i>GPAM</i> as a novel causative gene for cerebral palsy (CP) and led to the development of a CP mouse model with <i>GPAM</i> deficiency (<i>Gpam</i><sup><b>−</b>/<b>−</b></sup>). The model closely recapitulated the clinical phenotype of children with CP, due to the restricted proliferation of ASTs in the brain, reduced the amount of lipid, thinner brain white matter, and myelin dysplasia. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell proliferation and lipid synthesis. Cytosolic arginine sensor (CASTOR1) interacts with GATOR2 to regulate mTOR complex 1 (mTORC1). Targeted degradation of <i>CASTOR1</i> can activate the mTOR pathway. However, it remains unclear the involvement of mTOR pathway in neurological diseases such as CP. In this study, we demonstrated that the mTOR pathway was inhibited in <i>Gpam</i><sup><b>−</b>/<b>−</b></sup> mice. Notably, <i>CASTOR1</i> could regulate the activity of mTOR/S6K pathway, functioning as a negative upstream regulator. Furthermore, inhibition of <i>CASTOR1</i> upregulated mTOR/S6K signaling, promoting astrocyte proliferation and myelination, which in turn enhanced motor function in the <i>Gpam</i><sup><b>−</b>/<b>−</b></sup>-induced CP mouse model. Collectively, these findings reveal the role of astrocytic mTOR in the pathogenesis of CP mice, broaden the therapeutic strategies, and provide a promising candidate target for CP treatment.</p>

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Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam−/−-induced mouse model of cerebral palsy

  • 期刊论文

  • 发表日期：

    2025年4月15日

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  • Zhaofang Chen,
  • Liru Liu,
  • Xiaolin Guo,
  • Yage Zhang,
  • Mengru Zhong,
  • Yi Xu,
  • Tingting Peng Sr,
  • Tingting Peng Jr,
  • Yuan Zhang,
  • Qingfen Hou,
  • Danxia Fan,
  • Ting Gao,
  • Lu He,
  • Hongmei Tang,
  • Hao Hu,
  • Kaishou Xu

摘要

GPAM, a key enzyme for lipid synthesis, is predominantly expressed in astrocytes (ASTs), where it facilitates lipid supply for myelin formation. Our previous studies identified GPAM as a novel causative gene for cerebral palsy (CP) and led to the development of a CP mouse model with GPAM deficiency (Gpam−/−). The model closely recapitulated the clinical phenotype of children with CP, due to the restricted proliferation of ASTs in the brain, reduced the amount of lipid, thinner brain white matter, and myelin dysplasia. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell proliferation and lipid synthesis. Cytosolic arginine sensor (CASTOR1) interacts with GATOR2 to regulate mTOR complex 1 (mTORC1). Targeted degradation of CASTOR1 can activate the mTOR pathway. However, it remains unclear the involvement of mTOR pathway in neurological diseases such as CP. In this study, we demonstrated that the mTOR pathway was inhibited in Gpam−/− mice. Notably, CASTOR1 could regulate the activity of mTOR/S6K pathway, functioning as a negative upstream regulator. Furthermore, inhibition of CASTOR1 upregulated mTOR/S6K signaling, promoting astrocyte proliferation and myelination, which in turn enhanced motor function in the Gpam−/−-induced CP mouse model. Collectively, these findings reveal the role of astrocytic mTOR in the pathogenesis of CP mice, broaden the therapeutic strategies, and provide a promising candidate target for CP treatment.