Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.
Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.
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DOI：
10.1016/j.nbd.2022.105831
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发表时间：
2022-10-15
影响因子：
6.1
通讯作者：
Morrow, Eric M.
中科院分区：
文献类型：
--
作者：
Baytas, Ozan;Kauer, Julie A.;Morrow, Eric M.
关键词：
Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer’s disease and Parkinson’s disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder. The GPT2 enzyme regulates cell growth through replenishment of tricarboxylic acid (TCA) cycle intermediates and modulation of amino acid metabolism. In Gpt2-null mice, we observe an early loss of tyrosine hydroxylase (TH)-positive neurons in LC and reduced soma size at postnatal day 18. Gpt2-null LC shows selective positive Fluoro-Jade C staining. Neuron loss is accompanied by selective, prominent microgliosis and astrogliosis in LC. We observe reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord. Whole cell recordings in Gpt2-null LC slices show reduced soma size and abnormal action potentials with altered firing kinetics. Strikingly, we observe early decreases in phosphorylated S6 in Gpt2-null LC, preceding prominent p62 aggregation, increased LC3B-II to LC3B-I ratio, and neuronal loss. These data are consistent with a possible mechanism involving deficiency in protein synthesis and cell growth, associated subsequently with abnormal autophagy and neurodegeneration. As compared to the few genetic animal models with LC degeneration, loss of LC neurons in Gpt2-null mice is developmentally the earliest. Early neuron loss in LC in a model of human neurometabolic disease provides important clues regarding the metabolic vulnerability of LC and may lead to new therapeutic targets.
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影响因子：
12.7
作者：
Braak, Heiko;Del Tredici, Kelly
通讯作者：
Del Tredici, Kelly
影响因子：
16.2
作者：
Giaime E;Tong Y;Wagner LK;Yuan Y;Huang G;Shen J
通讯作者：
Shen J
现实世界的应力弹性与层层层的响应性有关。
影响因子：
16.6
作者：
Grueschow M;Stenz N;Thörn H;Ehlert U;Breckwoldt J;Brodmann Maeder M;Exadaktylos AK;Bingisser R;Ruff CC;Kleim B
通讯作者：
Kleim B
影响因子：
4.2
作者：
Grudzien, Aneta;Shaw, Pamela;Mesulam, M. Marsel
通讯作者：
Mesulam, M. Marsel
DOI：
10.1002/cne.23024
发表时间：
2012-06-15
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Bruinstroop E;Cano G;Vanderhorst VG;Cavalcante JC;Wirth J;Sena-Esteves M;Saper CB
通讯作者：
Saper CB