image: Johannes Schöneberg recently finished building one of the few existing AO-LLSM instruments. see more
Credit: Michelle Fredricks / UC San Diego
Researchers at the University of California, San Diego have received a $1.3 million grant from the WM Keck Foundation for a project that could help scientists better understand the role misfolded tau proteins play in causing of neurodegenerative diseases such as dementia, which may lead to more effective drug therapies.
The grant will go to three principal investigators of the project: Fleur Ferguson, Johannes Schöneberg and Gal Mishe. Ferguson and Schöneberg are assistant professors in the Department of Chemistry and Biochemistry; Mishe is an assistant professor at Halıcıoğlu Data Science Institute.
The lifetime risk of developing dementia is one in three, and it is currently estimated that nearly 6 million people suffer from some form of dementia in the United States alone. According to the World Health Organization, dementia is currently the seventh leading cause of death among all diseases and one of the leading causes of disability and dependency among older people worldwide. With no approved disease-modifying drug treatments currently available, there is an urgent and unmet clinical need for the growing patient population.
Accumulation of misfolded proteins concurrent with disease progression is a hallmark of neurodegenerative disorders known collectively as proteinopathies. Proteins are necessary for almost all cellular functions; when they are impaired, such as with misfolding, they can accumulate in protein aggregates and cause disease.
Tau proteins bind to and stabilize microtubules, which provide structure and shape to cells. Tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease, are linked to misfolding of tau proteins.
“We believe tau proteins are at the nexus of not only the pathology of Alzheimer’s disease, but other forms of neurodegenerative disease, including frontotemporal dementias. Learning to disrupt tau aggregation and promote its elimination further effective is an emerging new direction in research,” said Howard Feldman, dean of Alzheimer’s Disease Research and professor of neuroscience at the UC San Diego School of Medicine.
After 40 years of research, it is still unclear how different misfolded proteins contribute to the cause and progression of the disease. The team of interdisciplinary researchers at UC San Diego believes that the solution to the protein aggregation puzzle lies in fundamental biology that cannot be accessed by traditional methods and does not require a single type of ‘experience, but many types.
Each of the project’s principal investigators brings a unique perspective and expertise: Fleur Ferguson is a leader in targeted protein degradation; Johannes Schöneberg specializes in 4D subcellular imaging in brain organoids; and Gal Mishne, is an expert in high-dimensional data analysis and machine learning.
The WM Keck Foundation grant will allow them to do something new: reveal the role of tau protein aggregates within neurons in living tissue. By combining new small molecule targeting agents with advanced microscopy techniques, organoid cultures (constructed tissue samples that can be used to study aspects of a corresponding organ in a tissue culture dish) and machine learning, the team seeks to build an entirely new model of cellular health based on four-dimensional (4D) organelle dynamics in patient-derived brain organoids.
Ferguson, who holds a joint appointment as an assistant professor in the Skaggs schools of pharmacy and pharmaceutical sciences, developed much of the protein degradation framework that will be used for different species of tau aggregates. Ferguson will design, synthesize and apply protein degraders targeting FTD brain organoids in order to degrade diseased tau proteins.
Schöneberg, who holds a joint appointment as assistant professor in the School of Medicine’s Department of Pharmacology, will use CRISPR technology to tag key organelles in FTD stem cells with fluorescent proteins and image them in 4D at subcellular resolution while tau aggregates are degraded.
As an expert in adaptive optics lattice light sheet microscopy (AO-LLSM), Schöneberg recently completed the construction of one of the few existing AO-LLSM instruments. It is one of the most advanced fluorescence microscopes in the world and the adaptive optics provides the best high-resolution imaging for living tissue cells.
This 4D image, which includes the time dimension, will create 3 terabytes of data per hour. To analyze these data, Mishne will develop computational methods to analyze the structure and dynamics of mitochondrial networks extracted from AO-LLSM data. This will serve to quantify how the removal of tau aggregates affects cellular health.
“We hope to reveal, for the first time, how protein aggregates affect cellular health and, in doing so, create an entirely new experimental plan for measuring, quantifying and understanding organelle dynamics,” the team said. “By overcoming the long-standing disconnect between brain pathology and disease progression, our work will open new avenues for modeling, studying and treating disease across the spectrum of proteinopathies.”
The WM Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation’s largest philanthropic organizations, the WM Keck Foundation supports outstanding science, engineering and medical research. The Foundation also supports undergraduate education and maintains a program in Southern California to support arts and culture, education, health and community service projects.
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