South SFV Today

In 1992, Judith Frydman, PhD, discovered a molecular complex known as TRiC that plays a crucial role in folding proteins correctly within cells. This complex assists in shaping about 10% of human proteins into their necessary 3D structures. Recently, Frydman collaborated with Ingo Kurth, MD, from RWTH Aachen University, after he identified a mutation in one of TRiC's components in a child with intellectual disability and brain malformations.

The researchers investigated whether the TRiC mutation could be linked to the child's symptoms. Although dysfunctions in the complex have been associated with cancer and Alzheimer's disease, germline mutations had not previously been connected to developmental diseases. The team explored how this patient's mutation affected TRiC function using roundworms, baker's yeast, and zebrafish. They also reviewed genetic data from patients with similar neurodevelopmental defects and found 21 additional cases with mutations in seven of the eight components of TRiC.

The study introduced a new class of neurological diseases called "TRiCopathies," described in an article published on October 31 in Science. Frydman stated, "This opens a whole new way of thinking about the role of chaperones in brain development."

Patients identified by the researchers had one healthy copy of the TRiC gene alongside the mutated version. While some experienced muscular deficiencies, the primary effects were neurological. The research suggests an important role for this chaperone in brain development.

Research scientist Piere Rodriguez-Aliaga, PhD, co-first author on the study, created mutations in yeast versions of TRiC genes corresponding to human mutations linked to disease. Some mutations led to cell death while others did not, indicating varying effects based on mutation location within TRiC.

Further studies on roundworms and zebrafish revealed that having only the mutated CCT3 gene was lethal. Zebrafish with one mutated CCT3 showed brain development defects similar to those seen in humans.

Although it remains unclear which misfolded proteins may cause neurological symptoms, structural proteins like actin and tubulin are suspected due to their importance for cellular movement and stability.

Frydman and Rodriguez-Aliaga plan further studies on disease-linked mutations' mechanisms by examining how they affect protein folding using methods developed in their lab. They aim to use patient-derived cells grown into neurons or brain organoids for additional insights.

Rodriguez-Aliaga remarked, "This work is a nice example of basic science connecting with medicine."

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