From Soil Bacteria to Neurodegenerative Disorders
How a doctoral degree project helped to gain insights toward how we might combat Alzheimer’s. A Q&A with Charles River’s Hajo Schiewe
When Hajo Schiewe was doing his doctoral research on soil bacteria, he never thought it would one day figure in the fight against Alzheimer’s disease. But last month, a scientific journal published findings from cell-based assays indicating that a naturally occurring molecule produced in bacteria—the same molecule Schiewe had isolated more than 20 years ago—was able to exert a neuroprotective effect with key proteins involved in the progression of neurodegenerative diseases, notably Alzheimer’s disease. The study, which encompassed relatively similar findings from research groups in Korea and Germany, was published in Angewandte Chemie, the German Chemical Society’s peer-reviewed journal.
“The Concept of multiple discovery is on full display here,” said Hajo, now a Senior Director, Discovery Business Development at Charles River. “The fact that after 26 years two groups in Europe and Asia hit on the same indication and assay to find a neuroprotective property at roughly the same time is unreal.”
Eureka connected with Hajo to talk more about his doctoral research and how it morphed into something much bigger. This is part of our ongoing series, Research Notes, where our blog highlights the recently published work of our scientists.
Tell us more about collinolactone and your doctoral research?
Hajo: Collinolacton is a natural occurring molecule, a so-called polyketide. It is produced by a soil bacteria of the same genus that produces tetracycline, a commonly used antibiotic. I isolated it in 1997 during my PhD at the Institute of Organic Chemistry at the University of Goettingen and elucidated its chemical structure and the building blocks the bacteria synthesizes it from. It was named after the producing bacterial strain, Streptomyces collinus, and the lactone structural elements it contains. Back then it was just tested for antibacterial and antifungal activity and had shown none.
Eureka: But that is only part of the story, right?
Hajo: That’s right. Because of its unique structure and biosynthesis, collinolactone remained a topic of interest, and Professor Stephanie Ground’s group at the University of Tuebingen subsequently clarified its structure further, synthesized derivatives to gain insight into the structure-activity-relationship and kept testing it in various assays to identify if it had any relevant biological activity. Eventually collinolactone and one derivative were found to interfere with the assembly of microtubuli in the spindles that pull the chromosomes apart during cell division. The microtubuli in turn are stabilized by tau, a protein implicated in Alzheimer disease. This finding led to the formation of a research consortium to further investigate the properties of collinolactone in modulating protein aggregation.
Eureka: What did the Korean team discover?
Hajo: Recently, they described rhizolutin, a compound with an almost identical structure. A popular science article summarized the Korean group’s research this way, noting how it dissociated “amyloid-β (Aβ) plaques and tau tangles (fiber-like aggregates of tau proteins), both of which are typical hallmarks of Alzheimer’s disease. Such deposits form when amyloid-β proteins fold incorrectly to form β-sheets, which can aggregate to form insoluble plaques and fibers. These lead to the death of nerve cells, nerve inflammation, brain atrophy, and the cognitive losses these entail.”
Eureka: How was it determined the two compounds-- rhizolutin and collinolactone -- were the same?
Hajo: By comparing spectral data of rhizolutin with that of collinolactone the Tuebingen team confirmed that the two compounds are likely identical and that the structure described for collinolactone is the correct one. Building on the findings of the Korean team which showed neuroprotective properties for rhizolutin, the authoring research consortium evaluated collinolactone and its derivatives for their effect on limiting the damaging effect of oxidative stress on neurons, another hallmark of neurodegenerative diseases. Indeed, collinolactone increased cell viability in a dose-dependent manner, hinting at an additional tau- and Aβ-independent mechanism for neuroprotection. It is also worth noting that ONLY collinolactone and none of its derivatives shows that effect. This is another example of “nature does it best” and compounds isolated from natural sources are often the most optimized compounds of that type. Evolution did its work!
Eureka: So a lot of research is reflected in that paper in Angewandte Chemie.
Hajo: Yes. We initially set out in 1995 to show the incredible chemical diversity a single bacterial strain could produce. Following the philosophy that every molecule produced by nature has some kind of biological activity, all isolated molecules were tested in as many assays as possible. Via an assay for finding inhibitors of cell division it became clear that collinolactone interacted with cellular polymers, which are also involved in neurodegenerative diseases, notably Alzheimer’s. That led to a dedicated effort to evaluate collinolactone more broadly for neuroprotective properties and gain further insight into how it is achieving that. The paper describes the tau/Aβ-independent properties against oxidative stress as well as recapitulates findings of the Korean team re inhibition of Aβ aggregation.
Eureka: Who led the research described in the scientific paper cited above, how many different sites were involved, and what specifically did you contribute to these findings?
Hajo: The driving force behind it is Stephanie Grond, with the main work done by the main authors (Kerstin Frey, Matthias Schreiner, Jaime Felipe Guerrero Garzon) at their respective institutions. In total eight institutions contributed to the research described. I isolated collinolactone, named it (always the fun part!), elucidated its structure and published it in my dissertation (ISBN 3-932325-30-3). I also reviewed and amended manuscript drafts for this paper.
Eureka: Wow! How might the findings discussed in this paper lead to drugs to combat Alzheimer’s and other diseases of aging?
Hajo: The fact that collinolactone has shown efficacy in an in vivo model and was able to effect changes in the animal’s brains is encouraging as it demonstrates sufficient stability, bioavailability and the ability to cross the blood-brain-barrier, all prerequisites for the development of a CNS-active drug. A computational docking of collinolactone to tau and Aβ has identified putative binding sites which can be further exploited to identify additional binders and chemically synthesized. This allows for a broader chemical space to be explored around those binding sites and increases the chances to find a bioavailable, brain-penetrant, small molecule able to modulate plaque formation in Alzheimer’s patients. With that said, I would be reluctant to make any statement regarding its impact on other diseases of aging as the mechanism seems to be very specific to the Alzheimer-related tau and Aβ proteins.