Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.

Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS.

Publication date: Jun 10, 2019

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.

Manzo, E., , Lorenzini, Barrameda, D., O’Conner, A.G., Barrows, J.M., Starr, A., Kovalik, T., Rabichow, B.E., Lehmkuhl, E.M., Shreiner, D.D., Joardar, A., Li’evens, J.C., Bowser, R., Sattler, R., and Zarnescu, D.C. Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. 18272. 2019 Elife (8):

Concepts Keywords
ALS Branches of biology
Amyotrophic Lateral Sclerosis TARDBP
Drosophila Nervous system
Glia Amyotrophic lateral sclerosis
Glucose Glycolysis
Glucose Transporter Neuroscience
GLUT
Glycolysis
Locomotor
Metabolism
Motor Neurons
MRNA
Muscle
Nervous System
Neurodegenerative Disorder
Neuroprotective
Pathology
Pyruvate
Recycling
Sugar
Synaptic Vesicle
TDP

Semantics

Type Source Name
disease MESH multiple
gene UNIPROT SLC2A1
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
disease MESH defects
pathway BSID Glucose metabolism
disease MESH TDP-43 proteinopathy
gene UNIPROT TARDBP
disease MESH neurodegenerative disorder
disease MESH Amyotrophic Lateral Sclerosis
gene UNIPROT SOD1
gene UNIPROT IGFALS
disease DOID ALS
pathway BSID glycolysis
pathway BSID Glycolysis

Original Article

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