Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills.
Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills.
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DOI：
10.1038/s41598-017-12889-0
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发表时间：
2017-10-16
影响因子：
4.6
通讯作者：
Giulivi C
中科院分区：
文献类型：
--
作者：
Napoli E;Song G;Liu S;Espejo A;Perez CJ;Benavides F;Giulivi C
蛋白S-棕榈酰化是由棕榈酰酰基转移酶介导的可逆的翻译后修饰，棕榈酰酰基转移酶是一组含锌指DHHC结构域的蛋白（ZDHHC）。在这里，我们第一次证明了Zdhhc 13在携带自发Zdhhc 13隐性突变的小鼠模型（luc）中，在焦虑相关行为和运动功能以及大脑生物能量学中起着关键作用。在3个月的年龄，突变小鼠表现出增加的感觉运动门控，焦虑，活动减退，和减少运动协调，与同窝对照。Zdhhc 13的损失在皮层和小脑从3-和24米的杂合和纯合雄性突变小鼠导致较低水平的Drp 1 S-棕榈酰化伴随着改变线粒体动力学，增加糖酵解，β-aminolysis和乳酸酸中毒，和神经递质失衡。采用体内和体外模型，我们确定了Zdhhc 13依赖的Drp 1 S-棕榈酰化，其单独或协同作用，使正常发生的裂变融合过程。在体外和体内直接Zdhhc 13-Drp 1蛋白质相互作用的观察，确认Drp 1作为Zdhhc 13的底物。异常的分裂-融合过程导致线粒体形态和分布被破坏，不仅影响线粒体ATP输出，还影响神经传递和脑中突触结构的完整性，为Zdhhc 13缺陷小鼠中描述的行为异常奠定了基础。
Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase enzymes, a group of Zn2+-finger DHHC-domain-containing proteins (ZDHHC). Here, for the first time, we show that Zdhhc13 plays a key role in anxiety-related behaviors and motor function, as well as brain bioenergetics, in a mouse model (luc) carrying a spontaneous Zdhhc13 recessive mutation. At 3 m of age, mutant mice displayed increased sensorimotor gating, anxiety, hypoactivity, and decreased motor coordination, compared to littermate controls. Loss of Zdhhc13 in cortex and cerebellum from 3- and 24 m old hetero- and homozygous male mutant mice resulted in lower levels of Drp1 S-palmitoylation accompanied by altered mitochondrial dynamics, increased glycolysis, glutaminolysis and lactic acidosis, and neurotransmitter imbalances. Employing in vivo and in vitro models, we identified that Zdhhc13-dependent Drp1 S-palmitoylation, which acting alone or in concert, enables the normal occurrence of the fission-fusion process. In vitro and in vivo direct Zdhhc13-Drp1 protein interaction was observed, confirming Drp1 as a substrate of Zdhhc13. Abnormal fission-fusion processes result in disrupted mitochondria morphology and distribution affecting not only mitochondrial ATP output but neurotransmission and integrity of synaptic structures in the brain, setting the basis for the behavioral abnormalities described in the Zdhhc13-deficient mice.
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DOI：
10.1016/s1385-299x(96)00037-2
发表时间：
1997-08-01
期刊：
BRAIN RESEARCH PROTOCOLS
影响因子：
--
作者：
Borlongan, CV;Koutouzis, TK;Sanberg, PR
通讯作者：
Sanberg, PR
影响因子：
11.4
作者：
Germain, M;Mathai, JP;Shore, GC
通讯作者：
Shore, GC
影响因子：
4.2
作者：
Hamers, FPT;Koopmans, GC;Joosten, EAJ
通讯作者：
Joosten, EAJ
影响因子：
3.7
作者：
Cowin, Randi-Michelle;Bui, Nghiem;Paylor, Richard
通讯作者：
Paylor, Richard
影响因子：
4.8
作者：
Giulivi, Cecilia;Ross-Inta, Catherine;Pessah, Isaac N.
通讯作者：
Pessah, Isaac N.