Understanding the role of biomolecular condensates in brain health and disease

Biomolecular condensates (BMCs), such as the nucleolus, heterochromatin, or stress granules, are micron-scale, membrane-less, subcellular domains that exhibit liquid-like features. BMCs form droplets that coalesce through liquid-liquid phase separation (LLPS)–the same phenomenon that separates oil 🛢 and water 💧–and dynamically exchange molecules with the surrounding environment. Nervous system BMCs have many functions, including synaptic transmission, transcription regulation through stress granules, RNA splicing, and regulation of chromatin structure and gene expression. Aberrant condensate formation by LLPS is associated with many diseases, including cancer, infections, and neurodegeneration.

Despite the emerging importance of BMCs in neuroscience, there are very few tools available to monitor and manipulate BMCs in vivo in the nervous system. Establishment of new tools that exploit advances in imaging, optogenetic, chemogenetic, biophysical, single molecule, or other strategies would (1) enable in vivo BMC monitoring and manipulation and (2) provide much needed insight into BMC nervous system functions.

In 2021, the NIH Blueprint for Neuroscience Research established an initiative to support the development of innovative tools and technologies to explore nervous system BMCs. The goal of this program was to study BMCs in vivo and enable investigators to adopt these tools to answer outstanding questions in basic neuroscience to transform understanding of the mechanistic role of BMCs in human nervous system health and disease and serve as the foundation for the development of novel BMC-based therapeutics.

Through the funding opportunity RFA-DA-22-008, later reissued as RFA-DA-24-039, NIH Blueprint for Neuroscience Research: Tools and Technologies to Explore Nervous System Biomolecular Condensates (R21 Clinical Trial Not Allowed), nine projects were funded for over $3.1M. Projects are using cutting-edge methods like new optogenomics and chemogenetic tools, single molecule tracking, and advanced imaging techniques (e.g., Fluorescence Recovery After Photobleaching, or FRAP, and cryogenic electron tomography, or cryoET) to characterize BMCs and their effects on disease-states like amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia, and Alzheimer’s disease. To date, over 35 publications have resulted from this exciting initiative!

For more information on other research areas supported by the NIH Blueprint for Neuroscience Research, please visit the NIH Blueprint Research Initiatives webpage: Blueprint Research Initiatives | Blueprint #NIHBlueprint20