0
0
Stanford, CA — A groundbreaking study led by Stanford Medicine has identified a new class of neurological disorders tied to mutations in a crucial protein-folding complex, offering new insights into the causes of developmental disorders, seizures, and intellectual disabilities.
For decades, scientists have known the importance of protein folding in the body. In 1992, Stanford biologist Judith Frydman, PhD, uncovered a molecular complex known as TRiC (TCP-1 Ring Complex), essential for folding proteins correctly in cells. TRiC helps shape thousands of human proteins, guiding their transformation into functional three-dimensional structures. This complex is vital, as approximately 10% of all proteins pass through TRiC’s barrel-like structure.
Despite the well-established role of protein chaperones like TRiC, their malfunction was not widely associated with developmental diseases—until now. Frydman’s recent collaboration with pediatrician Ingo Kurth, MD, from RWTH Aachen University in Germany, uncovered an unexpected connection between TRiC mutations and a child suffering from intellectual disability, seizures, and brain malformations.
Until this discovery, mutations in TRiC had only been linked to cancer and Alzheimer’s disease. The idea that mutations in this complex could cause developmental diseases had not been considered, as proteins rely on TRiC to fold correctly in order to function. Researchers assumed that defects in protein folding would likely be fatal.
Frydman and her team joined forces with Kurth’s lab and other collaborators at Washington University School of Medicine in St. Louis, Missouri, to investigate this rare case. By studying the mutation in CCT3, one of TRiC’s components, in various organisms—such as roundworms, baker’s yeast, and zebrafish—the team began to unravel the connection between faulty TRiC function and neurological issues.
While reviewing genetic databases, the team discovered 21 more patients exhibiting similar symptoms of intellectual disability and developmental delays, all carrying mutations in seven of TRiC’s eight subunits. The findings, recently published in Science, have led the team to coin the term “TRiCopathies” to describe this new class of neurological diseases.
“This opens a whole new way of thinking about the role of chaperones in brain development,” said Frydman, who is a senior author of the study.
The mutations identified in TRiC are inherited in a manner where patients possess one healthy copy of the gene and one mutated copy. This is consistent with the essential nature of TRiC—two defective copies would likely be fatal. Interestingly, the primary impact of these mutations appears to be neurological, with some patients also exhibiting muscular deficiencies. This suggests that TRiC plays a particularly important role in brain development.
Researcher Piere Rodriguez-Aliaga, PhD, co-first author of the study, found that the mutations in yeast cells corresponding to the human mutations caused some cells to die, while others survived but showed abnormalities. Similar results were seen in roundworms and zebrafish, with affected animals displaying developmental issues, particularly in brain development.
Though the exact proteins causing the neurological symptoms are still unclear, the researchers suspect that structural proteins like actin and tubulin, which are folded by TRiC and are critical for cellular stability and movement, could be involved. In the affected organisms, misfolded proteins were found to accumulate, causing defects in cellular function, including damage to mitochondria, which are essential for neuronal function.
The discovery of TRiCopathies is a pivotal moment in understanding how protein folding defects can lead to neurological disorders. The researchers plan to continue exploring the mechanisms behind these mutations, using advanced techniques to study protein folding in the lab and patient-derived cells that can be transformed into brain cells.
“This work is a great example of basic science merging with clinical applications,” Rodriguez-Aliaga said. “Without years of fundamental research on protein folding, this discovery wouldn’t have been possible.”
This research opens new possibilities for diagnosing and treating a variety of developmental neurological disorders, shedding light on the previously unexplored role of protein chaperones in brain health.
Reference:
“Brain malformations and seizures by impaired chaperonin function of TRiC” by Florian Kraft, Piere Rodriguez-Aliaga, Weimin Yuan, Lena Franken, Kamil Zajt, and others, Science, October 31, 2024. DOI: 10.1126/science.adp8721.
