2023 Research Update: Catalyst for a Cure Initiative to Prevent and Cure Neurodegeneration

The Melza M. and Frank Theodore Barr Foundation Catalyst for a Cure Initiative to Prevent and Cure Neurodegeneration began their investigations in 2022.

The principal investigators in the Catalyst for a Cure Initiative to Prevent and Cure Neurodegeneration (CFC4), pictured clockwise from left, are Humsa Venkatesh, PhD (Brigham and Women’s Hospital), Milica Margeta, MD, PhD (Mass Eye and Ear), Sandro Da Mesquita, PhD, (Mayo Clinic), and Karthik Shekhar, PhD (University of California, Berkeley).

Launched in July 2022, the fourth in Glaucoma Research Foundation’s Catalyst for a Cure series pursues one of our most confounding medical challenges: how to prevent and cure diseases that, like glaucoma, Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), occur when key cells in the central nervous system deteriorate and die — a process known as neurodegeneration.

Overall research goals

Diseases of the central nervous system (CNS) affect millions of people worldwide by causing irreversible functional impairment and death. These diseases have many causes, may manifest as early-onset or late-onset, and exhibit a diverse range of patient symptoms and tissue changes. However, they also have common features: they can share genetic predispositions, are commonly associated with ageing, and their hallmarks are loss of neurons and abnormalities in the local “microenvironment”, consisting of blood vessels, immune cells and glial cells. Such microenvironmental abnormalities may be the common denominator shared by all CNS diseases, despite apparent differences in their manifestations. Our goal is to use cutting-edge and interdisciplinary approaches to discover these commonalities, creating a bold new intellectual space to explore therapies that target them.

The Catalyst for a Cure 4 team will focus on three major CNS diseases that collectively affect more than 150 million people worldwide: glaucoma, Alzheimer’s disease (AD), and gliomas. Glaucoma is an optic neuropathy that leads slowly, but relentlessly to permanent blindness. Alzheimer’s disease (AD) is the most common form of dementia, a devastating group of mental disorders that lead to accelerated loss of cognitive abilities, poor reasoning and memory, and generalized brain dysfunction. Gliomas are the most aggressive forms of brain tumors. They occur among all age groups, are difficult to treat and are quick to recur, leading to severe disabilities that are most often fatal.

Each of these three diseases affects different subpopulations of neurons in distinct part of the CNS. Yet, they all share several common microenvironmental hallmarks that cause neurons to degenerate and die. By studying these diseases in tractable animal models, and analyzing the results together rather than separately, we intend to discover these common hallmarks.

Our team (Da Mesquita, Margeta, Shekhar and Ventakesh) bring together a diverse set of expertise spanning neurological diseases, research areas, and techniques. To discover the hallmarks of neurodegeneration, we will apply state-of-the-art genomic profiling technologies and data-driven techniques to analyze the disease microenvironment in great detail. We will utilize different rodent disease models as well as primary tissues collected from human patients. Ultimately, we expect to unravel both distinct and common cellular and molecular pathway changes across these conditions that can be further used for more efficient diagnoses, prognoses, and treatments for different neurodegenerative diseases.

Midyear Progress Report, March 2023

Our efforts thus far have focused on optimizing the key genomic profiling technique called “single cell RNA Sequencing” (scRNAseq) that we will use to analyze the microenvironment in rodent disease models of glaucoma, AD, and brain tumors. As we are analyzing non-neuronal cell types in three different tissues (retina, optic nerve, and brain), our first goal was to establish that this technique is robust and reproducible in our hands. To that effect, the Da Mesquita lab has conducted two sets of experiments to validate the technique in the three tissues of interest: 1) cell isolation followed by validation of isolated cell populations using a technique called flow cytometry, which showed promising results, and 2) cell isolation from normal mouse retinas, optic nerves, and brains followed by scRNAseq. We are now awaiting the results of the scRNAseq experiment, which should be available in the next few weeks.

In the interim, Margeta and Venktash labs (both based in Boston) have initiated the purchase of relevant equipment and supplies to be able to replicate the experimental approach utilized by the Da Mesquita lab. (In order to be able to compare data obtained across all the labs, it is critical to consistently deploy the same cell isolation, processing, and scRNAseq analysis techniques.) We would like to thank Glaucoma Research Foundation for generously providing funding for the cell dissociator that the two Boston labs will share to conduct this series of experiments. After pilot scRNAseq results obtained by the De Mesquita lab have been analyzed, we will utilize the same approach (or optimize it, if necessary) to ensure we can obtain the same high-quality data in our labs before applying them to mouse models of glaucoma and brain tumors.

The Shekhar lab will be performing the scRNAseq computational analysis of the pilot experiment performed by the Da Mesquita lab as soon as the data are available, as described above. Dr. Shekhar has also began obtaining already published scRNAseq datasets of brain tissues from patients with AD, other neurologic diseases and relevant animal models, and will analyze these datasets to identify cellular pathways that are altered across various CNS diseases. Finally, the Shekhar lab has initiated a fruitful collaboration with a member of the CFC3 consortium, Dr. Xin Duan. This collaboration involves development and validation of a technique called “spatial transcriptomics”, which enables detection of changes in many genes simultaneously in thin sections of the retina while perfectly preserving spatial organization. Once optimized in normal retinas, this powerful technique will be applied to retinas from glaucoma rodent models.

Following successful deployment and optimization of the scRNAseq methodology across eye and brain tissues in the participating labs, we will use this technique to detect changes in microenvironment in mouse models of AD, glaucoma, and brain tumors, and subsequently validate our findings in human tissues. With this approach we expect to find common cellular and molecular pathways that are altered across the three diseases, with the hope that this information will lead to development of novel therapeutic approaches for these devastating neurodegenerative conditions.

This research update report was posted on March 29, 2023.