First Link Identified Between ‘Pathological Condensates’ and Microcephaly; Yale Team Develops Platform

U.S. researchers have identified for the first time an association between dysfunction in intracellular biomolecular condensates and neurodevelopmental disorders, including microcephaly.

According to Yale School of Medicine on the 3rd (local time), a research team at the school developed a platform called CondenScreen to identify genes associated with dysfunction in biomolecular condensates. The findings were published on the 25th of last month in the international journal Molecular Biology of the Cell.

Biomolecular condensates are distinct compartments formed when biological molecules cluster together inside cells without a membrane. Some condensates become dysfunctional and accumulate abnormally. These pathological condensates are known to trigger cell death and are associated with neurodegenerative diseases such as frontotemporal degeneration, Parkinson’s disease and Alzheimer’s disease.

The research team screened 20,000 genes in the human genome for those that prevent the accumulation of pathological condensates. The researchers removed genes one at a time in cultured cells and observed whether pathological condensates formed.

As a result, many of the top candidate genes were found to be associated with neurodevelopmental disorders. These disorders include microcephaly, a rare condition in which the head is abnormally small.

Study first author Dylan Porch, a doctoral student in Yale’s Department of Molecular Biophysics and Biochemistry, said, “To our knowledge, neurodevelopmental disorders and pathological condensates have not been linked before,” calling it “a very exciting discovery.”

Study lead Christian Schlieker said that pathological condensates accumulate over decades in neurodegenerative diseases, while neurodevelopmental disorders emerge rapidly, within months. “Such rapid changes in condensates are very unusual,” he explained.

The research team also used CondenScreen to evaluate about 2,000 small molecules in search of drug candidates for dystonia (DYT1). In the process, they identified several promising compounds approved by the U.S. Food and Drug Administration (FDA).

“Many proteins associated with neurological diseases are difficult to target with existing pharmacology,” Porch said. “If biomolecular condensates themselves can be targeted, that opens a new path for therapeutic applications.”

The research team is currently screening tens of thousands of additional compounds, and CondenScreen has been made available online.