Principal investigator: Dr Federico Herrera, University of Lisbon (Portugal)
Lay summary:
Spastic Ataxia 8 (SPAX8) is a rare inherited neurological disorder that affects movement, balance, and muscle control. It is caused by mutations (changes) in a gene called NKX6-2, which plays a key role in the development of oligodendrocytes – specialised brain cells responsible for producing myelin. Myelin is the protective coating that allows nerve cells to send signals efficiently. In people with SPAX8, myelin is reduced or abnormal, but the exact reason why this happens is still unclear.
This project aims to understand how mutations in the NKX6-2 gene disrupt the formation and function of oligodendrocytes. To do this, the research team will use an innovative laboratory approach that converts easily accessible skin cells from people with SPAX8 into oligodendrocyte-like cells. They will use these oligodendrocyte-like cells to investigate how mutations in NKX6-2 prevent oligodendrocytes from functioning as they should.
By clarifying how SPAX8 alters brain cell function, the researchers believe this project will create a valuable model for future research. Ultimately, they hope the research will help identify targets for new therapies aimed at restoring myelin and improving neurological function in affected individuals.
Scientific summary:
Spastic ataxia 8 (SPAX8) is caused by loss-of-function mutations in the NKX6-2 gene. These pathogenic variants disrupt the development and maintenance of myelin. These researchers hypothesise that SPAX8-associated NKX6-2 mutations impair oligodendrocyte differentiation and function by disrupting the transcriptional programs required for oligodendroglial maturation and myelin production. The researchers aim to determine whether SPAX8-causing NKX6-2 variants interfere with the transdifferentiation of human fibroblasts into oligodendrocytes. They plan to characterise oligodendrocyte functional abnormalities caused by mutations in NKX6-2, distinguishing defects in differentiation efficiency from defects in the biology of cells that do differentiate. They aim to identify transcriptomic pathways altered by SPAX8-associated NKX6-2 mutations through RNA sequencing of reprogrammed oligodendrocytes and to validate selected changes by targeted low-throughput assays.
The research team hopes these aims will enable them to establish a human platform for future therapeutic studies aimed at restoring oligodendrocyte maturation and remyelination in SPAX8.
This project was made possible by a generous donation from the DVS Foundation.
