Diet matters: Calcium and magnesium’s role in neurodegenerative diseases
The body needs a touch of a heavy metal, called manganese, to keep the cells alive and functioning correctly. When a person is exposed to too much, however, an illness known as manganism can arise, leaving patients with progressive symptoms, including tremors and difficulty walking, that are similar to those associated with Parkinson’s disease. A WSU research group conducted meticulous dietary studies of a model organism—the fruit fly—and uncovered something surprising: the common dietary supplements calcium and magnesium reduced the toxic effects of manganese in affected flies and increased their lifespans.
The findings do not mean that popping a few calcium and magnesium pills will cure manganism or Parkinson’s disease, but they do put a needed focus on dietary trace metals and their impact on neurodegenerative diseases, according to biology professor Mark VanBerkum, whose group conducted the work. "Expanding the knowledge base is what helps researchers consider new ideas for treatments and drug companies investigate new targets to develop drugs," he said. "That is the relevance of basic research like this."
The manganese connection
VanBerkum said his interest in manganese began after learning about the work of fellow WSU biology professor David Njus, who is investigating manganism, Parkinson’s disease and other neurodegenerative diseases and their link to dysfunction in cell organelles. When working properly, organelles called lysosomes act as important disposal systems, VanBerkum described. Manganese, however, can interfere with the lysosomes’ ability to do their job and allows certain proteins to accumulate abnormally, which has a cascade effect leading to the death of key nerve cells (dopaminergic neurons) and the appearance of symptoms.
This was intriguing on several levels, VanBerkum said. For one, his very first study as a student was on an aluminum toxicity model of Alzheimer’s disease, so he had a keen interest in metals’ effects on the body. For another, he was looking for research suited to undergraduate students in his lab and a project centering on manganism sounded like a good option.
Fruit flies are sensitive to excessive levels of dietary manganese, showing mobility problems similar to those seen in manganism and Parkinson’s disease and dying young. His idea was for his students to investigate whether low levels of dietary manganese (5 millimolar/ mM) also caused early mortality. It turned out that the fly’s diet mattered. Notably, those fed a cornmeal diet died much younger overall than those fed a molasses diet, even when the level of manganese was the same.
Chef to the fruit filies
A key to the research in Mark VanBerkum’s lab is the WSU Drosophila Facilities, affectionately known as "the fly kitchen," managed by the departmental technician Charles Hogan. In fact, VanBerkum said, Hogan provided an important clue to experiments that ultimately showed how calcium and magnesium had an impact on a neurodegenerative condition (see main article).
Hogan makes the food for fruit flies (in the scientific genus Drosophila) for several labs on campus, typically using city water to prepare one of the fly foods. "Charlie told us he used Detroit tap water to make the molasses fly food and that was really helpful because it led us to finding that the tap water was a big contributor of calcium and magnesium," he explained. "That was a big contribution."
For Hogan, that is all in a day’s work. "Over the course of a year, I make tens of thousands of vials and thousands of bottles of meticulously prepared food, which is critical for maintaining the health and research viability of the Drosophila populations across these labs," he described. For VanBerkum’s project alone, Hogan prepared over 60 gallons of fly food, provided training on the preparation, proper handling and storage of specialized fly foods and implemented rigorous quality-control measures to ensure that the mineral concentrations in the foods were consistent across batches.
"The good thing about this job is that at times it does present an opportunity to really get involved with the research end. I have participated in many studies that required different diets, different chemicals and a variety of things," Hogan added. "I do look forward to these different challenges. It keeps the job more interesting."
Drilling into diet
One of the students, Zahraa Ghosn, asked to take the study further and figure out why. After some brainstorming and guidance from VanBerkum, Ghosn set up experiments to determine whether other metals within the different fly foods were interacting with the manganese and providing a protective effect. That involved tracking mortality among manganese-treated and untreated fruit flies fed on cornmeal, molasses and sucrose-yeast diets and contrasting the metal content in each diet. "Experiments like these involve very simple assays, but students have to be very persistent and come in every Monday, Wednesday, Friday to count, so it is a big effort," VanBerkum said, noting that other undergraduate students in the lab assisted with the counts and other lab work.
The effort paid off. Ghosn found that flies lived longer if their food contained higher levels of calcium and magnesium. "That was a surprising result," VanBerkum said. "It suggested that calcium and magnesium are involved in the uptake or use of manganese, so it no longer has its deleterious effects."
All of the undergraduate students who are listed as co-authors on the paper, which was published in January 2024, have now graduated and are moving forward with their careers, VanBerkum said. With new undergraduates, his lab is also now moving forward, but on the manganese-calcium-magnesium connection. "The beauty of fruit flies is that they have mutations in practically every gene and you can easily order and buy these mutants. We now have a series of flies with mutations in a variety of transporters (metals that metabolize manganese), including zinc, magnesium and calcium and we’ve begun screening them to identify which mutations are important in terms of how much manganese is absorbed into the body through diet, but also how much is excreted via the Malpighian tubules, or the ‘kidney’ of a fly," he explained. "We are already having some success and when we’re ready, we hope to go back and look in the fly brains to see if the dopaminergic neurons are dead."
VanBerkum hopes this research will influence other research groups pursuing similar lines of study. "Our results showing the effects of calcium and magnesium told us not only about the calcium and magnesium connection, but also why researchers doing similar work need to start looking into and describing exactly what is in the diet, including the presence of all these potentially interacting metals. This should be a basic part of experimental design."
Resources: Ghosn, Z. A., et al. "Divalent metal content in diet affects severity of manganese toxicity in Drosophila," Biology Open, vol. 13, no. 1, January 15, 2024, doi: 10.1242/bio.060204.
By Leslie Mertz