Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.
Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.
复制标题
DOI：
10.1016/j.molmet.2022.101468
复制
发表时间：
2022-06
影响因子：
8.1
通讯作者：
Kalb RG
中科院分区：
文献类型：
--
作者：
Riechers SP;Mojsilovic-Petrovic J;Belton TB;Chakrabarty RP;Garjani M;Medvedeva V;Dalton C;Wong YC;Chandel NS;Dienel G;Kalb RG
Abstract Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful. Our work is the first to perform a comprehensive and quantitative analysis of intermediary metabolism in neurons in the setting of fALS causing gene products. Because the cardinal feature of ALS is death of motor neurons, these new studies are directly relevant to the pathogenesis of ALS. Our functional interrogations begin to unpack how metabolic re-wiring is induced by fALS genes and it will be very interesting, in the future, to gain insight in amino acid fueling of the TCA cycle. We suspect pleiotropic effects of amino acid fueling, and this may lead to very targeted therapeutic interventions.
登录
查看更多内容
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1073/pnas.0402026101
发表时间：
2004-07-27
影响因子：
11.1
作者：
Dupuis, L;Oudart, H;Loeffler, JP
通讯作者：
Loeffler, JP
DOI：
10.3109/21678421.2014.959024
发表时间：
2014-12
影响因子：
2.8
作者：
Abe K;Itoyama Y;Sobue G;Tsuji S;Aoki M;Doyu M;Hamada C;Kondo K;Yoneoka T;Akimoto M;Yoshino H;Edaravone ALS Study Group
通讯作者：
Edaravone ALS Study Group
影响因子：
13.6
作者：
DeBerardinis RJ;Chandel NS
通讯作者：
Chandel NS
影响因子：
3.7
作者：
Drechsel, Derek A.;Estevez, Alvaro G.;Barbeito, Luis;Beckman, Joseph S.
通讯作者：
Beckman, Joseph S.