SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction.
SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction.
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DOI：
10.1093/hmg/ddac063
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发表时间：
2022-08-23
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传性痉挛性截瘫15型（HSP 15）是一种神经退行性疾病，由无法产生SPG 15蛋白引起，从而导致溶酶体肿胀。然而，溶酶体畸变和神经元死亡之间的联系很少探索。为了揭示溶酶体畸变在疾病发病机制中的功能后果，我们分析了来自HSP 15患者的人真皮成纤维细胞以及源自SPG 15敲除（KO）小鼠模型的原代皮质神经元。我们发现，SPG15蛋白丢失诱导缺陷的顺行运输，受损的轴突生长，轴突肿胀和减少自噬流量与溶酶体异常的发病。此外，我们观察到脂质积累内的溶酶体室，表明细胞脂质稳态的扭曲与溶酶体的变化交织在一起。我们进一步证明，SPG15 KO神经元表现出突触功能障碍，伴随着增强的脆弱性谷氨酸诱导的兴奋性毒性。总的来说，我们的研究建立了溶酶体畸变，脂质代谢和电生理损伤之间的密切联系，这表明溶酶体缺陷是在HSP 15中的多种神经退行性疾病过程的核心。
Hereditary spastic paraplegia type 15 (HSP15) is a neurodegenerative condition caused by the inability to produce SPG15 protein, which leads to lysosomal swelling. However, the link between lysosomal aberrations and neuronal death is poorly explored. To uncover the functional consequences of lysosomal aberrations in disease pathogenesis, we analyze human dermal fibroblasts from HSP15 patients as well as primary cortical neurons derived from an SPG15 knockout (KO) mouse model. We find that SPG15 protein loss induces defective anterograde transport, impaired neurite outgrowth, axonal swelling and reduced autophagic flux in association with the onset of lysosomal abnormalities. Additionally, we observe lipid accumulation within the lysosomal compartment, suggesting that distortions in cellular lipid homeostasis are intertwined with lysosomal alterations. We further demonstrate that SPG15 KO neurons exhibit synaptic dysfunction, accompanied by augmented vulnerability to glutamate-induced excitotoxicity. Overall, our study establishes an intimate link between lysosomal aberrations, lipid metabolism and electrophysiological impairments, suggesting that lysosomal defects are at the core of multiple neurodegenerative disease processes in HSP15.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
3.3
作者：
Hirst J;Borner GH;Edgar J;Hein MY;Mann M;Buchholz F;Antrobus R;Robinson MS
通讯作者：
Robinson MS
影响因子：
7.7
作者：
Jakobs, Maximilian A. H.;Dimitracopoulos, Andrea;Franze, Kristian
通讯作者：
Franze, Kristian
DOI：
10.1093/brain/aww111
发表时间：
2016-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Kara E;Tucci A;Manzoni C;Lynch DS;Elpidorou M;Bettencourt C;Chelban V;Manole A;Hamed SA;Haridy NA;Federoff M;Preza E;Hughes D;Pittman A;Jaunmuktane Z;Brandner S;Xiromerisiou G;Wiethoff S;Schottlaender L;Proukakis C;Morris H;Warner T;Bhatia KP;Korlipara LV;Singleton AB;Hardy J;Wood NW;Lewis PA;Houlden H
通讯作者：
Houlden H
影响因子：
1.5
作者：
Kimura, Shunsuke;Noda, Takeshi;Yoshimori, Tamotsu
通讯作者：
Yoshimori, Tamotsu