Increased glucose, transformed into energy, could give people with amyotrophic lateral sclerosis, or ALS, improved mobility and a longer life, according to new findings by a University of Arizona-led research team.
Physicians have long known that people with ALS experience changes in their metabolism that often lead to rapid weight loss in a process called hypermetabolism.
According to the study’s lead author Ernesto Manzo, a UA alumnus and postdoctoral researcher in the Department of Molecular and Cellular Biology, hypermetabolism can be a relentless cycle.
People with ALS use more energy while resting than those without the disease, while simultaneously they often struggle to effectively make use of glucose, the precise ingredient a body needs to make more energy.
Experts have not known exactly what happens in a patient’s cells to cause this dysfunction or how to alleviate it.
“This project was a way to parse out those details,” said Manzo, who described the results, published online in eLife, as “truly shocking.”
The study revealed that when ALS-affected neurons are given more glucose, they turn that power source into energy.
With that energy, they’re able to survive longer and function better.
Increasing glucose delivery to the cells, then, may be one way to meet the abnormally high energy demands of ALS patients.
“These neurons were finding some relief by breaking down glucose and getting more cellular energy,” Manzo said.
ALS is almost always a progressive disease, eventually taking away patients’ ability to walk, speak and even breathe.
The average life expectancy of an ALS patient from the time of diagnosis is two to five years.
“ALS is a devastating disease,” said Daniela Zarnescu, UA professor of molecular and cellular biology and senior author on the study.
“It renders people from functioning one day to rapidly and visibly deteriorating.”
Previous studies on metabolism in ALS patients have focused primarily on what happens at the whole-body level, not the cellular level, Zarnescu explained.
“The fact that we uncovered a compensatory mechanism surprised me,” Zarnescu said. “These desperate, degenerating neurons showed incredible resilience. It is an example of how amazing cells are at dealing with stress.”
The novelty of the findings partially lies in the fact that metabolism in ALS patients has remained poorly understood, Zarnescu said.
“It’s difficult to study, in part because of limited accessibility to the nervous system,” she said.
Because scientists can’t scrape away neurons from the brain without causing irreparable damage to a patient, the researchers used fruit flies as a model.
“Fruit flies can teach us a lot about human diseases,” Manzo said.
In the lab, he and Zarnescu used high-powered microscopes to observe the motor neurons of fruit flies in their larval state, paying close attention to what happened as they provided more glucose.
They found that when they increased the amount of glucose, the motor neurons lived longer and moved more efficiently.
When the researchers took glucose away from the neurons, the fruit fly larva moved more slowly.
Their findings were consistent with a pilot clinical trial, which found a high carbohydrate diet was one possible intervention for ALS patients with gross metabolic dysfunction.
“Our data essentially provide an explanation for why that approach might work,” Zarnescu said. “My goal is to convince clinicians to perform a larger clinical trial to test this idea.”
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the central nervous system (CNS).
Approximately 10% of all familial cases of ALS are due to mutations in the gene encoding cytosolic copper–zinc superoxide dismutase (SOD1) (1).
Similar to patients with ALS, transgenic mice that express the mutant human SOD1 protein (e.g., SOD1G93A mice) display progressive motor neuron degeneration, muscular atrophy, and a shortened lifespan (2).
Although the exact mechanisms and pathological processes responsible for the initiation and progression of motor neuron degeneration remain largely unknown (3), it is becoming increasingly clear that the disorder’s basis is multimodal (4).
Acidosis is a feature of several neuropathological conditions including ischemia, epilepsy, Parkinson disease, and multiple sclerosis (5–7).
In ALS, an acidic environment has the potential to catalyze the onset and/or progression of several disease features including diminished glutamate reuptake (8), mitochondrial vacuolization (9), glial cell activation (10), endoplasmic reticulum stress (11), and impaired oxidative phosphorylation/ATP synthesis (12).
Acidosis also activates acid-sensing ion channels (ASICs), which, when excessively stimulated, promote intracellular Ca2+ influx, neuroinflammation, axonal degeneration, demyelination, and neuronal death—features of several mouse disease models (6, 7), including ALS.
Interestingly, gene expression profiling studies showed significant up-regulation (2- to 10-fold) of ASIC2 (also known as amiloride-sensitive cation channel neuronal 1; ACCN1) and ASIC3 (ACCN3) in laser-captured motor neurons from patients with ALS harboring mutations in SOD1 (13), suggesting that acidosis occurs in patients with ALS.
In agreement, significant up-regulation of ASIC2 expression was recently noted in the spinal cords of patients with sporadic ALS and SOD1G93Amice (14).
Metabolic acid-base disorders are classically identified by measuring the concentrations of plasma or serum electrolytes that affect H+ concentration.
A strong ion difference (SID), the summed ion concentrations of all strong base minus all strong acid, is a major determinant of H+concentration. In healthy mammals, SID has a positive value of about 40 mEq/L (15).
The apparent SID (SIDapp), which does not take into account the role of weak acids in determining SID, is calculated as [Na+] + [K+] + [Mg2+] + [Ca2+] − [Cl−] − [lactate]. A more complex Eq. (1,000 × 2.46 × 10−11 × pCO2/(10−pH) + [albumin] × (0.12 × pH − 0.631) + [phosphate] × (0.309 × pH − 0.469), the effective SID (SIDeff), incorporates the contribution of weak acids derived from carbon dioxide (CO2), proteins (albumin), and phosphate.
The difference between SIDapp and SIDeff is called the strong ion gap (SIG), and represents the contribution of unmeasured (i.e., unidentified) ions to the SID.
SIG values are reportedly a strong predictor of mortality in individuals exposed to pathological acidosis (16), with the unidentified ions perhaps passing from liver into blood (17). It is not known if disease-related changes in SIDapp, SIDeff, or SIG manifest during development of ALS.
Pathological acidosis can be averted through compensatory mechanisms such as (i) lowering acid production (e.g., down-regulating glycogenolysis and glycolysis to inhibit lactate synthesis from glycogen), (ii) promoting acid elimination through increased respiration and renal excretion, and (iii) resynthesis of acids back into substrate stores (18).
Interestingly, gene expression studies on laser-captured motor neurons from patients with ALS showed reduced mRNA levels of α-glucosidase, an enzyme that degrades glycogen to glucose (13). Similar studies on laser-captured astrocytes from SOD1G93A mice also demonstrated more than twofold increases in glycogen synthase mRNA (19).
Therefore, we have now investigated whether SOD1G93A mice undergo metabolic changes favoring development of acidosis and whether they display disease-related pH changes in the CNS.
Further, we examined whether the disease course affects the concentration of ions responsible for the SIDapp, SIDeff, and SIG, and whether SOD1G93A mice display compensatory increased glycogen or modifications in α-glucosidase activity to avert acidosis. We also examined human ALS autopsied cervical spinal cord for changes in glycogen content and α-glucosidase activity to determine whether the mouse data are relevant for humans.
More information: Ernesto Manzo et al, Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS, eLife (2019). DOI: 10.7554/eLife.45114
Journal information: eLife
Provided by University of Arizona
