Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), c/o Sapienza University, Rome, Italy
Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), c/o Sapienza University, Rome, Italy.
Life Sci Alliance. 2020 Oct 26;3(12). doi: 10.26508/lsa.202000799. Print 2020 Dec.
Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the gene encoding the microtubule-severing protein spastin. We hypothesise that -HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy. However, until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient-derived cells, thus revealing novel therapeutic targets for the treatment of -HSP.
遗传性痉挛性截瘫（HSP）是一种神经退行性疾病，最常见的病因是编码微管切割蛋白 spastin 的基因发生常染色体显性突变。我们假设 -HSP 是由于单倍不足导致 spastin 功能降低所致；因此，提高野生型 spastin 等位基因水平的治疗方法可能是一种有效的治疗方法。然而，到目前为止，spastin 水平是如何调节的还很大程度上未知。在这里，我们表明激酶 HIPK2 可调节增殖细胞、分化神经元和体内 spastin 蛋白水平。我们的工作揭示了 HIPK2 介导的 spastin 在 S268 处的磷酸化可抑制 K554 处的 K48 多聚泛素化和防止其依赖 neddylation 的蛋白酶体降解。在 spastin RNAi 神经元细胞模型中，过表达 HIPK2 或抑制 neddylation 可恢复 spastin 水平并挽救神经突缺陷。值得注意的是，我们证明通过抑制 HSP 中 spastin 小鼠模型和患者来源细胞中的 neddylation 介导的降解，可在神经元中恢复 spastin 水平，从而揭示了治疗 -HSP 的新治疗靶点。
