A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.
A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.
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DOI：
10.1186/s40478-020-01043-z
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发表时间：
2020-10-15
影响因子：
7.1
通讯作者：
Roberts RC
中科院分区：
文献类型：
--
作者：
Edgar JR;Ho AK;Laurá M;Horvath R;Reilly MM;Luzio JP;Roberts RC
LITAF的常染色体显性突变导致罕见的脱髓鞘性周围神经病变，Charcot-Marie-Tooth病1C型（CMT 1C）。LITAF蛋白在许多人类细胞类型中表达，我们使用共聚焦和电子显微镜研究了CMT 1C患者的原代成纤维细胞中两种不同LITAF突变的后果。我们观察到晚期内吞隔室（晚期内体和溶酶体）出现空泡化/扩大。在从对照人成纤维细胞或CMT 1C患者来源的细胞中敲除LITAF后也观察到这种空泡化，这与CMT 1C成纤维细胞中功能丧失突变的结果一致。空泡化类似于先前在来自CMT 4J患者的成纤维细胞中观察到的空泡化，CMT 4J患者具有图4中的常染色体隐性突变。FIG 4蛋白是磷酸肌醇激酶复合物的组分，其在晚期内体的界膜上合成磷脂酰肌醇3，5-二磷酸。磷脂酰肌醇3，5-二磷酸通过阳离子通道TRPML 1激活溶酶体Ca 2+的释放，这是维持哺乳动物细胞内体和溶酶体稳态所必需的。我们观察到TRPML 1的小分子激活剂ML-SA 1能够拯救LITAF敲除、FIG 4敲除和CMT 1C患者成纤维细胞的空泡化表型。我们的数据描述了脱髓鞘CMT的两种不同亚型共有的第一种细胞表型，并且与LITAF和FIG 4在维持晚期内体和溶酶体的稳态所需的共同内溶酶体途径上起作用一致。虽然我们的实验是对人类成纤维细胞，他们对我们的理解的分子发病机制和方法的治疗方法在两个亚型的脱髓鞘腓骨肌萎缩症的影响。
Autosomal dominant mutations in LITAF are responsible for the rare demyelinating peripheral neuropathy, Charcot–Marie–Tooth disease type 1C (CMT1C). The LITAF protein is expressed in many human cell types and we have investigated the consequences of two different LITAF mutations in primary fibroblasts from CMT1C patients using confocal and electron microscopy. We observed the appearance of vacuolation/enlargement of late endocytic compartments (late endosomes and lysosomes). This vacuolation was also observed after knocking out LITAF from either control human fibroblasts or from the CMT1C patient-derived cells, consistent with it being the result of loss-of-function mutations in the CMT1C fibroblasts. The vacuolation was similar to that previously observed in fibroblasts from CMT4J patients, which have autosomal recessive mutations in FIG4. The FIG4 protein is a component of a phosphoinositide kinase complex that synthesises phosphatidylinositol 3,5-bisphosphate on the limiting membrane of late endosomes. Phosphatidylinositol 3,5-bisphosphate activates the release of lysosomal Ca2+ through the cation channel TRPML1, which is required to maintain the homeostasis of endosomes and lysosomes in mammalian cells. We observed that a small molecule activator of TRPML1, ML-SA1, was able to rescue the vacuolation phenotype of LITAF knockout, FIG4 knockout and CMT1C patient fibroblasts. Our data describe the first cellular phenotype common to two different subtypes of demyelinating CMT and are consistent with LITAF and FIG4 functioning on a common endolysosomal pathway that is required to maintain the homeostasis of late endosomes and lysosomes. Although our experiments were on human fibroblasts, they have implications for our understanding of the molecular pathogenesis and approaches to therapy in two subtypes of demyelinating Charcot–Marie–Tooth disease.
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影响因子：
21.3
作者：
Medina DL;Di Paola S;Peluso I;Armani A;De Stefani D;Venditti R;Montefusco S;Scotto-Rosato A;Prezioso C;Forrester A;Settembre C;Wang W;Gao Q;Xu H;Sandri M;Rizzuto R;De Matteis MA;Ballabio A
通讯作者：
Ballabio A
影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
DOI：
10.1111/j.1600-0854.2009.00915.x
发表时间：
2009-07
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
de Lartigue J;Polson H;Feldman M;Shokat K;Tooze SA;Urbé S;Clague MJ
通讯作者：
Clague MJ
影响因子：
4.5
作者：
Bissig, Christin;Hurbain, Ilse;van Niel, Guillaume
通讯作者：
van Niel, Guillaume
腓骨肌萎缩症相关蛋白 SIMPLE 与内体运输中的 ESCRT 机制一起发挥作用。
DOI：
10.1083/jcb.201204137
发表时间：
2012-11-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee SM;Chin LS;Li L
通讯作者：
Li L