Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
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DOI：
10.1186/s40478-020-01088-0
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发表时间：
2020-12-07
影响因子：
7.1
通讯作者：
Li XJ
中科院分区：
文献类型：
--
作者：
Mou Y;Dong Y;Chen Z;Denton KR;Duff MO;Blackstone C;Zhang SC;Li XJ
遗传性痉挛性截瘫（HSP）是由长皮质脊髓神经元的长度依赖性轴突病变引起的，但这些皮质投射神经元（PN）的轴突如何退化仍然是一个谜。我们产生了与SPG3A（最常见的早发性常染色体显性HSP）相关的两个ATL 1错义突变的同基因人多能干细胞（hPSC）系。在hPSC衍生的皮质PN中，ATL 1突变导致轴突生长减少，轴突运输受损，轴突肿胀累积，重现疾病特异性表型。重要的是，ATL1突变失调蛋白脂质基因表达，减少星形胶质细胞中的脂滴大小，并意外地破坏胆固醇从神经胶质细胞转移到神经元，导致SPG3A皮质PN中胆固醇缺乏。应用来自对照星形胶质细胞的胆固醇或条件培养基，脑中胆固醇的主要来源，挽救了SPG3A皮质PN中的异常轴突运输和轴突再生。此外，用NR1H2激动剂GW 3965治疗纠正了SPG3A星形胶质细胞中的脂滴缺陷，并促进了胆固醇从星形胶质细胞中流出，导致胆固醇水平的恢复和SPG3A皮质PN中轴突变性的拯救。这些结果揭示了神经胶质细胞胆固醇稳态受损介导的皮质PNs轴突变性的非细胞自主机制。
Hereditary spastic paraplegias (HSPs) are caused by a length-dependent axonopathy of long corticospinal neurons, but how axons of these cortical projection neurons (PNs) degenerate remains elusive. We generated isogenic human pluripotent stem cell (hPSC) lines for two ATL1 missense mutations associated with SPG3A, the most common early-onset autosomal dominant HSP. In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal outgrowth, impaired axonal transport, and accumulated axonal swellings, recapitulating disease-specific phenotypes. Importantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unexpectedly disrupted cholesterol transfer from glia to neurons, leading to cholesterol deficiency in SPG3A cortical PNs. Applying cholesterol or conditioned medium from control astrocytes, a major source of cholesterol in the brain, rescued aberrant axonal transport and swellings in SPG3A cortical PNs. Furthermore, treatment with the NR1H2 agonist GW3965 corrected lipid droplet defects in SPG3A astrocytes and promoted cholesterol efflux from astrocytes, leading to restoration of cholesterol levels and rescue of axonal degeneration in SPG3A cortical PNs. These results reveal a non-cell autonomous mechanism underlying axonal degeneration of cortical PNs mediated by impaired cholesterol homeostasis in glia.
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影响因子：
5.3
作者：
Kandan, Nicholas M.;Pigino, Gustavo F.;Brady, Scott T.;Lazarov, Orly;Binder, Lester I.;Morfini, Gerardo A.
通讯作者：
Morfini, Gerardo A.
影响因子：
5.2
作者：
Denton, Kyle R.;Lei, Ling;Grenier, Jeremy;Rodionov, Vladimir;Blackstone, Craig;Li, Xue-Jun
通讯作者：
Li, Xue-Jun
影响因子：
3.9
作者：
Falk, Julia;Rohde, Magdalena;Beetz, Christian
通讯作者：
Beetz, Christian
DOI：
10.1038/nrn2946
发表时间：
2011-01
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Blackstone C;O'Kane CJ;Reid E
通讯作者：
Reid E
影响因子：
8.3
作者：
Cui X;Chopp M;Zacharek A;Cui Y;Roberts C;Chen J
通讯作者：
Chen J