New genetic disorder can cause early aging and cognitive impairment

The discovery story began with the study of a family whose young members exhibited atypical symptoms: hair graying at an early age, loss of motor skills, and intellectual deficits. Unlike known progeria syndromes, where cognitive functions are often preserved, this condition led to severe neuropathy. Through the use of recessive trait mapping, scientists discovered a mutation in the IVNS1ABP gene. Until then, this gene had never been associated with biological aging processes or neurological pathologies.

To study the mechanisms of the disease, the scientists turned the patients’ skin cells into induced pluripotent stem cells, and then into neural precursor cells. During the observations, it was found that the mutant cells grew significantly more slowly than the healthy ones. The reason for the slowdown was the cells’ entry into a senescent state, also known as the “zombie” state, in which the cell stops dividing but does not die, while releasing inflammatory markers. The study identified three different indicators of genome damage and increased expression of the CDKN2A gene, which is a well-known inhibitor of the cell cycle.

Further experiments showed that DNA damage occurs directly at the moment of cell division. The scientists established a link between the mutation and the proteins responsible for actin, one of the main structural components of the cytoskeleton. During mitosis, actin filaments should form a smooth and symmetrical ring to divide the cell into two parts. In the patients’ cells, this ring was deformed and shriveled. Due to the irregular shape of the ring, the division process was asymmetric, leading to critical damage to the genetic material and the death of neurons.

An important step in the research was to test the possibility of correcting the defect. The researchers discovered that using specific chemicals to stabilize the actin structure could normalize the rate of cell division, even in mutant models. This finding suggests that understanding the molecular mechanism of the disease could lead to the development of targeted treatments.

This study highlights the tremendous potential of using stem cell models derived from patients to study rare and previously unknown pathologies. The researchers plan to continue their work on animal models to confirm the effectiveness of actin stabilization in preventing cognitive decline and signs of premature aging in living organisms.