Shulin Ju, a Brandeis postdoc under the direction of Professors Gregory Petsko (BCHM) and Dagmar Ringe (BCHM), aided in a study that has found a potential use for the previously rejected drug latrepirdine, a discovery that may eventually help millions of people with neurodegenerative conditions.
In collaboration with researchers at the Mount Sinai School of Medicine in New York, Ju’s work was published in August in “Molecular Psychiatry.” John Steele, a graduate student in the Gandy group, Lenard Lachenmayer, a postdoc in the Yue lab and Ju share the first authorship of this new publication.
Having worked at the Rosenstiel Basic Biomedical Research Center for the past seven years, Ju was originally drawn to Brandeis because of his appreciation of the projects, great support from PIs, and outstanding training environment in the Petsko-Ringe lab.
Ju explained that latrepirdine was initially used in Russia as an anti-histamine.
“People also found that this compound has neuro-protective function. Based on its effects on cognition in rodents and its highly favorable safety profile, the compound entered clinical trials in the U.S. for both Alzheimer’s disease and Huntington’s disease,” Ju said.
Yet, the trials failed. Ju and his collaborators reexamined the issue. “We were trying to identify molecular targets of the compound, so we can understand better the contradictory results from trials in the U.S. and in Russia.” Using yeast models of several neurodegenerative disease associated proteins, Ju discovered that latrepirdine does have its merits. It can specifically reduce the toxicity of alpha-synuclein by inducing autophagy. Autophagy is a tightly regulated process performed by the cell, during which the cell “self-eats” its own proteins or damaged organelles. Mount Sinai Researchers, led by professors Sam Gandy and Zhenyu Yue, showed a similar finding in cell culture and in the brains of mice.
If proven useful beyond yeast and mice, this compound “might yield clinical benefit for synucleinopathies, the hallmark of which is accumulation of alpha-synuclein, including Parkinson’s disease, Lewy body dementia, rapid eye movement (REM), sleep disorder and/or multiple system atrophy,” as reported in “Molecular Psychiatry.”
Ju explained that one likely reason the trials with latrepirdine did not work in the U.S. is that they were testing the wrong patients. “They most likely used the wrong sample for the clinical trials. If a subgroup of patients that had accumulation of alpha-synuclein in the brain had been chosen, the result might be different.” Ju also said that as this study moves forward it may be subject to improvement, including the design of a more specific and effective compound.
Ju also published in “Molecular Psychiatry,” his other work with latrepirdine. While less involved with this study, Ju played a role in the discovery that latrepirdine can improve cognition and arrest progression of neuropathology in an Alzheimer’s mouse model. For a compound previously labeled as a failure, Mount Sinai and Brandeis researchers have helped prove that it may eventually be a valuable addition to the field of medicine.
Ju described that successfully navigating the science world is time consuming. While this article was published this August, “this study was initiated years back by Mount Sinai Researchers.”
While these discoveries may potentially benefit people worldwide, it has also helped Ju personally. “My career goal is to be a professor, to do research in lab, and to teach students in a classroom. With the addition of this published study, I hope I am one step closer to have my own independent lab, continuing my research on neurodegenerative disease”.
