Driving the Next Generation of Neurodegeneration Research

By 2050, an estimated 12 million Americans will struggle with neurodegenerative diseases such as Alzheimer’s, ALS, and Parkinson’s. The Chan Zuckerberg Initiative (CZI) is bringing together researchers early in their careers and from diverse fields to develop bold new ideas to help tackle this public health crisis.

As part of CZI’s Neurodegeneration Challenge Network (NDCN), we are funding 16 projects for the second phase of our Collaborative Pairs Program. In the first phase of Collaborative Pairs, 30 pairs of labs were funded for 18-month pilot projects to catalyze new collaborations and develop novel approaches to understand the fundamental biology of neurodegenerative diseases. In the second phase, 16 of these projects were selected for grants to support expanded four-year projects. Many teams will engage additional collaborators who will contribute expertise in fields such as machine learning, computational analysis, CRISPR screening, visual system circuit analysis, new disease models, epigenomic analysis, and cryo-electron microscopy. We’re excited to support these projects because we believe the only way to solve these devastating diseases is by developing interdisciplinary and transformative approaches to neurodegenerative disease.

Read on to hear from a few of our grantees about how their projects are accelerating our understanding of neurodegenerative diseases, and view the full list of Collaborative Pairs projects.

Understanding Neurodegenerative Disease in Pediatric Patients

Cells from patients with TBCK-related neurodegeneration show increased markers of lysosomes and dextran uptake, which suggests altered intracellular transport and degradation. Photo courtesy of Dr. Rebecca Ahrens-Nicklas and Dr. Elizabeth Bhoj.

“We’ve seen how applying targeted treatment to specific genetic syndromes can change fatal neurodegenerative disorders into chronic manageable conditions. I’m so excited that we’re on the cusp of taking those discoveries and making them applicable to a wide range of neurodegeneration patients.” — Dr. Elizabeth Bhoj

While neurodegenerative diseases like Alzheimer’s are typically viewed as diseases of aging, studies show that they can impact anyone, including kids. Dr. Rebecca Ahrens-Nicklas and Dr. Elizabeth Bhoj study pediatric neurodegenerative diseases, which often arise from defects in a single cellular pathway. Pediatric neurodegeneration presents a unique opportunity to explore which cellular processes initiate and drive these diseases in children — offering insight into the source of neurodegenerative disease in adults.

In the first phase of their studies, Rebecca and Elizabeth identified candidate genes for new mechanisms of neurodegeneration. In the second phase of their study, they will research how these genes cause neurodegenerative diseases in children and their potential application to adult conditions. The pair have added collaborator Dr. Marylyn Ritchie in the second phase of study. An expert in biobank bioinformatics, Marylyn will help the team expand their findings in pediatrics to adult populations as well.

At the Intersection of Aging and Genetics, We Find TDP-43

The Ward/Ori team uses short-lived turquoise killifish to study how aging increases the risk of neurodegenerative diseases. Photo courtesy of FLI / Nadine Grimm.

“The opportunity to exchange and combine our points of view, technologies, and network of collaborations has transformed our teams and laid the foundation for our next phase of research.” — Dr. Alessandro Ori

Aging and genetics are the two most prominent risk factors for neurodegeneration and likely act together to drive disease. However, it has historically been challenging to study their contributions to disease simultaneously. The partnership between Dr. Michael Ward and Dr. Alessandro Ori investigates how aging and genetics work synergistically to drive disease. Building on their initial research, their second phase of the project will focus on identifying genes that ensure important proteins like TDP-43 get where they need to be in a cell since mislocalization of this protein is an accepted but poorly understood hallmark at the center of multiple neurodegenerative diseases. By conducting studies in a vertebrate model organism with a short lifespan, they’ll be able to answer questions about how the effects of key mutations are exacerbated by aging. Their work will also contribute to the Chan Zuckerberg CELLxGENE platform and napari hub plugins to facilitate the application of their findings to other organisms, including humans. To build upon single-cell transcriptomics and functional genomic expertise, the pair have added collaborators Dr. Hemali Phatnani and Dr. Lars Steinmetz in the second phase of study.

Identifying How the Gut-Brain Axis May Contribute to Parkinson’s Disease

Image of brain microglia. Photo courtesy of Dr. Javier Rueda-Carrasco.

“At the beginning, it was just an idea. Now, two years in, we have an amazing team of young scientists and students working with us to understand the body-brain connection in an innovative manner.” — Dr. Soyon Hong

Did you know there is an entire nervous system beyond the brain and spinal cord … in the gut! The cells across these nervous systems, called the gut-brain axis, are in constant communication with one another. Dr. Soyon Hong and Dr. Tim Bartels are fascinated by the two-way biochemical signaling between the gastrointestinal tract and the central nervous system (the gut-brain axis) and how it may contribute to Parkinson’s disease. Their project studies how resident gut immune cells may contribute to brain diseases and, if so, where and how immune cell functions become abnormal in Parkinson’s patients. This could create new pathways for therapeutic intervention to stop the disease before it damages the brain.

As part of their work to analyze the gut-brain axis from all angles, Soyon and Tim have recruited key collaborative experts in proteomics, lysosomal biology, and cryogenic electron microscopy for the second phase of their research. The pair have also added collaborators Dr. Dario Alessi, Dr. Kenneth Harris, and Dr. Neil Ranson in the second phase of study to scale their team of experts.

Using Optical Pooled Screening Technology as a Model for Neurodegenerative Research

The Lagier-Tourenne/Blainey team shows how optical pooled screens enable screening for genetic factors that perturb a cell’s structure and behavior by simultaneously imaging both the cell morphology (left) and genetic perturbations (right). Photo courtesy of Jake Qiu, Dr. Su Min Lim and Dr. Owen Andrews.

“This work will expand our basic understanding of neurodegeneration and, in turn, nominate new therapeutic hypotheses to impact patient outcomes.” -Dr. Paul Blainey

How do we identify new strategies for treatments of neurodegenerative diseases? Dr. Clotilde Lagier-Tourenne and Dr. Paul Blainey are developing a platform to discover new therapeutic targets for ALS and frontotemporal dementia. Their research uses optical genetic screens, which combine high-quality imaging with in-situ sequencing analysis.

In their first phase of study, Clotilde and Paul worked to discover how neurodegenerative diseases impact the appearance of a cell and its organelles. In this next phase, they are expanding this research to new cellular systems most relevant to disease. They are using optical pooled screening technology in neurons made from induced pluripotent stem cells, which can then be used as a model for further research on neurodegenerative diseases. Through this technology, it’s possible to screen for genetic perturbations that change a cell’s structure or behavior, helping identify new disease mechanisms more efficiently. The pair have added collaborator Dr. Ankur Jain in this second phase of study.

Learn more about CZI’s work in neurodegeneration.

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Supporting the science and technology that will make it possible to cure, prevent, or manage all diseases by the end of the century.