Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model.
Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model.
复制标题
DOI：
10.1038/s41467-022-34679-7
复制
发表时间：
2022-11-23
影响因子：
16.6
通讯作者：
Newton, Alexandra C.
中科院分区：
文献类型：
--
作者：
Lorden, Gema;Wozniak, Jacob M.;Dore, Kim;Dozier, Lara E.;Cates-Gatto, Chelsea;Patrick, Gentry N.;Gonzalez, David J.;Roberts, Amanda J.;Tanzi, Rudolph E.;Newton, Alexandra C.
蛋白激酶 C (PKC) 同工酶的精确调节活性对于维持细胞稳态至关重要。功能丧失突变通常与癌症相关，而一种同工酶 PKCα 的功能获得变异则与阿尔茨海默病 (AD) 相关。在这里，我们表明，一种变体 PKCα M489V 的增强活性足以重新连接大脑磷酸蛋白质组、驱动突触变性并损害小鼠模型的认知。这种变体在不改变开/关激活动力学或稳定性的情况下使催化活性适度增加 30%，强调增强的催化活性足以驱动观察到的生化、细胞和最终认知效应。对 PKCα M489V 小鼠海马神经元的分析表明，与野生型小鼠相比，淀粉样蛋白 β 诱导的突触抑制增强，脊柱密度降低。行为研究表明，这种突变本身就足以损害认知，并且当与 AD 小鼠模型结合时，会进一步加速认知能力下降。蛋白激酶的成药性使 PKCα 成为 AD 的一个有前途的治疗靶点。增强蛋白激酶 C α (PKCα) 活性的突变与阿尔茨海默病有关。在这里，作者报告说，一种变体 PKCα M489V 的增强活性足以重新连接大脑磷酸化蛋白质组、驱动突触变性并损害小鼠模型的认知。
Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis. Whereas loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isozyme, PKCα, are associated with Alzheimer’s disease (AD). Here we show that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. This variant causes a modest 30% increase in catalytic activity without altering on/off activation dynamics or stability, underscoring that enhanced catalytic activity is sufficient to drive the biochemical, cellular, and ultimately cognitive effects observed. Analysis of hippocampal neurons from PKCα M489V mice reveals enhanced amyloid-β-induced synaptic depression and reduced spine density compared to wild-type mice. Behavioral studies reveal that this mutation alone is sufficient to impair cognition, and, when coupled to a mouse model of AD, further accelerates cognitive decline. The druggability of protein kinases positions PKCα as a promising therapeutic target in AD. Mutations that enhance the activity of protein kinase C alpha (PKCα) are associated with Alzheimer’s Disease. Here, the authors report that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model.
登录
查看更多内容
影响因子：
2.9
作者：
Chaput, Dale;Kirouac, Lisa Hornbeck;Bell-Temin, Harris;Stevens, Stanley M., Jr.;Padmanabhan, Jaya
通讯作者：
Padmanabhan, Jaya
影响因子：
64.5
作者：
Antal CE;Hudson AM;Kang E;Zanca C;Wirth C;Stephenson NL;Trotter EW;Gallegos LL;Miller CJ;Furnari FB;Hunter T;Brognard J;Newton AC
通讯作者：
Newton AC
影响因子：
64.5
作者：
BEACH, ME;HAWKINS, RD;MAYFORD, M
通讯作者：
MAYFORD, M
DOI：
10.1037/h0077579
发表时间：
1979-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
BARNES, CA
通讯作者：
BARNES, CA
DOI：
10.1111/ejn.12499
发表时间：
2014-04
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Alfonso S;Kessels HW;Banos CC;Chan TR;Lin ET;Kumaravel G;Scannevin RH;Rhodes KJ;Huganir R;Guckian KM;Dunah AW;Malinow R
通讯作者：
Malinow R