AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2023 Aug 26

PMID 37627248

Authors

Ines Belo Do Nascimento

Gamze Ates

Nathalie Desmet

Pauline Beckers

Ann Massie

Emmanuel Hermans

Affiliations

Soon will be listed here.

Abstract

Alterations in the activity of the regulator of cell metabolism AMP-activated protein kinase (AMPK) have been reported in motor neurons from patients and animal models of amyotrophic lateral sclerosis (ALS). Considering the key role played by astrocytes in modulating energy metabolism in the nervous system and their compromised support towards neurons in ALS, we examined whether a putative alteration in AMPK expression/activity impacted astrocytic functions such as their metabolic plasticity and glutamate handling capacity. We found a reduced expression of AMPK mRNA in primary cultures of astrocytes derived from transgenic rats carrying an ALS-associated mutated superoxide dismutase (hSOD1). The activation of AMPK after glucose deprivation was reduced in hSOD1 astrocytes compared to non-transgenic. This was accompanied by a lower increase in ATP levels and increased vulnerability to this insult, although the ATP production rate did not differ between the two cell types. Furthermore, soliciting the activity of glutamate transporters was found to induce similar AMPK activity in these cells. However, manipulation of AMPK activity did not influence glutamate transport. Together, these results suggest that the altered AMPK responsiveness in ALS might be context dependent and may compromise the metabolic adaptation of astrocytes in response to specific cellular stress.

References

Winkler U, Seim P, Enzbrenner Y, Kohler S, Sicker M, Hirrlinger J . Activity-dependent modulation of intracellular ATP in cultured cortical astrocytes. J Neurosci Res. 2017; 95(11):2172-2181. DOI: 10.1002/jnr.24020. View

Gowans G, Hawley S, Ross F, Grahame Hardie D . AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013; 18(4):556-66. PMC: 3791399. DOI: 10.1016/j.cmet.2013.08.019. View

Belo Do Nascimento I, Verfaillie M, Ates G, Beckers P, Joris V, Desmet N . AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport. Cells. 2022; 11(11). PMC: 9180554. DOI: 10.3390/cells11111800. View

Allen S, Hall B, Woof R, Francis L, Gatto N, Shaw A . C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain. 2019; 142(12):3771-3790. PMC: 6906594. DOI: 10.1093/brain/awz302. View

Lei H, Dirren E, Poitry-Yamate C, Schneider B, Gruetter R, Aebischer P . Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. J Cereb Blood Flow Metab. 2018; 39(7):1283-1298. PMC: 6668519. DOI: 10.1177/0271678X18756499. View

Grahame Hardie D, Schaffer B, Brunet A . AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2015; 26(3):190-201. PMC: 5881568. DOI: 10.1016/j.tcb.2015.10.013. View

Voss C, Pajecka K, Stridh M, Nissen J, Schousboe A, Waagepetersen H . AMPK Activation Affects Glutamate Metabolism in Astrocytes. Neurochem Res. 2015; 40(12):2431-42. DOI: 10.1007/s11064-015-1558-5. View

Browne S, Yang L, DiMauro J, Fuller S, Licata S, Beal M . Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS. Neurobiol Dis. 2006; 22(3):599-610. DOI: 10.1016/j.nbd.2006.01.001. View

Howland D, Liu J, She Y, Goad B, Maragakis N, Kim B . Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002; 99(3):1604-9. PMC: 122237. DOI: 10.1073/pnas.032539299. View

10.

Jelluma N, Yang X, Stokoe D, Evan G, Dansen T, Haas-Kogan D . Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res. 2006; 4(5):319-30. DOI: 10.1158/1541-7786.MCR-05-0061. View

11.

Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W . The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006; 1762(11-12):1068-82. DOI: 10.1016/j.bbadis.2006.05.002. View

12.

Rothstein J, Martin L, Kuncl R . Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med. 1992; 326(22):1464-8. DOI: 10.1056/NEJM199205283262204. View

13.

Granatiero V, Sayles N, Savino A, Konrad C, Kharas M, Kawamata H . Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1 astrocytes. Autophagy. 2021; 17(12):4029-4042. PMC: 8726657. DOI: 10.1080/15548627.2021.1899682. View

14.

Chen L, Xin F, Wang J, Hu J, Zhang Y, Wan S . Conserved regulatory elements in AMPK. Nature. 2013; 498(7453):E8-10. DOI: 10.1038/nature12189. View

15.

Domise M, Vingtdeux V . AMPK in Neurodegenerative Diseases. Exp Suppl. 2016; 107:153-177. DOI: 10.1007/978-3-319-43589-3_7. View

16.

Maksimovic K, Youssef M, You J, Sung H, Park J . Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models. Biomolecules. 2023; 13(5). PMC: 10216611. DOI: 10.3390/biom13050863. View

17.

Ravera S, Bonifacino T, Bartolucci M, Milanese M, Gallia E, Provenzano F . Characterization of the Mitochondrial Aerobic Metabolism in the Pre- and Perisynaptic Districts of the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2018; 55(12):9220-9233. DOI: 10.1007/s12035-018-1059-z. View

18.

Lederer C, Torrisi A, Pantelidou M, Santama N, Cavallaro S . Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis. BMC Genomics. 2007; 8:26. PMC: 1796866. DOI: 10.1186/1471-2164-8-26. View

19.

Yamanaka K, Komine O . The multi-dimensional roles of astrocytes in ALS. Neurosci Res. 2017; 126:31-38. DOI: 10.1016/j.neures.2017.09.011. View

20.

Maixner D, Yan X, Gao M, Yadav R, Weng H . Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain. Anesthesiology. 2015; 122(6):1401-13. PMC: 4439367. DOI: 10.1097/ALN.0000000000000619. View