Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation

• DOI: 10.1016/j.celrep.2016.02.051
• Publication Date: 2016-03-10T17:25:28Z
• Authors: Yuming Wang; Jace Jones-Tabah; Probir Chakravarty; Aengus Stewart; Alysson Muotri; Rebecca R. Laposa; Jesper Q. Svejstrup
• Keywords: Cockayne syndrome; Ectopic expression

Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of B (CSB) affects neuronal gene expression differentiation, so we attempted to bypass its function expressing downstream target genes. Intriguingly, ectopic Synaptotagmin 9 (SYT9), key component the machinery controlling neurotrophin release, bypasses need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF), implicated differentiation synaptic modulation, pharmacological mimics such as 7,8-dihydroxyflavone amitriptyline can compensate deficiency cell models well. SYT9 BDNF are downregulated CS patient brain tissue, further indicating that sub-optimal signaling underlies neurological defects CS. In addition shedding light on cellular mechanisms underlying pointing future avenues intervention, these data suggest an important role differentiation.