Cockayne syndrome is a very rare autosomal recessive hereditary disorder characterized by a broad spectrum of clinical manifestations such as neurodegeneration, premature ageing, developmental disorders, photosensitivity, short stature and other symptoms. The number of new cases per year (annual incidence) in European countries is close to one person per 200,000 inhabitants.⁽¹⁾ The vast majority of patients have mutations in Cockayne protein B.⁽²⁾ Cockayne syndrome B (CSB), triggered by as yet unknown mechanisms, can affect the brain, where it manifests clinically as microcephaly, mental retardation and demyelination.

Baby with microcephaly, a serious disability.
Graphic: Centers for Disease Control and Prevention. Wikipedia.

For their investigations, the researchers used three-dimensional brain spheroids - spherical structures that they had developed from induced pluripotent stem cells (hiPSC) from CSB patients.

The researchers discovered that Cockayne protein B deficiency led to impaired cell migration due to defective autophagy as an explanation for clinical microcephaly on the one hand, while on the other hand mental retardation could have been caused by altered neuronal network functionality and neurotransmitter GABA levels, indicating a disrupted GABA switch that probably impairs the formation of brain circuits. In addition, impaired maturation of the oligodendrocytes is a possible cause of the demyelination observed in children with COD. In healthy people, most nerve fibers are surrounded by a multi-layered fatty sheath (lipoprotein), the myelin layer. This enables nerve signals (electrical impulses) to be transmitted quickly and accurately along the nerve fiber. If the myelin of the nerve cells is destroyed, the impulses can no longer be transmitted correctly.⁽³⁾

The scientists also observed that impaired migration and oligodendrocyte maturation could be partially restored by pharmacological HDAC inhibition.

Original publication:
Kapr J, Scharkin I, Ramachandran H, Westhoff P, Pollet M, Dangeleit S, Brockerhoff G, Rossi A, Koch K, Krutmann J & Fritsche E. (2024).  HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B. Cell Mol Life Sci. 2024 Aug 23;81(1):368. doi: 10.1007/s00018-024-05406-w. PMID: 39179905; PMCID: PMC11343962.

Further information on Cockayne syndrome B:
(1) https://www.orpha.net/de/disease/detail/191
(2) Spyropoulou Z, Papaspyropoulos A, Lagopati N, Myrianthopoulos V, Georgakilas AG, Fousteri M, Kotsinas A, Gorgoulis VG. Cockayne Syndrome Group B (CSB) (2021). The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer. Cells. 2021 Apr 10;10(4):866. doi: 10.3390/cells10040866. PMID: 33920220; PMCID: PMC8068816.
(3) https://www.msdmanuals.com/de-de/heim/st%C3%B6rungen-der-hirn-r%C3%BCckenmarks-und-nervenfunktion/multiple-sklerose-ms-und-verwandte-st%C3%B6rungen/%C3%BCberblick-%C3%BCber-demyelinisierende-erkrankungen