Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation

Yuming Wang; Jace Jones-Tabah; Probir Chakravarty; Aengus Stewart; Alysson Muotri; Rebecca R Laposa; Jesper Q Svejstrup

doi:10.1016/j.celrep.2016.02.051

Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation

Cell Rep. 2016 Mar 22;14(11):2554-61. doi: 10.1016/j.celrep.2016.02.051. Epub 2016 Mar 10.

Authors

Yuming Wang¹, Jace Jones-Tabah², Probir Chakravarty³, Aengus Stewart³, Alysson Muotri⁴, Rebecca R Laposa², Jesper Q Svejstrup⁵

Affiliations

¹ Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UK.
² Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
³ Bioinformatics & Biostatistics Group, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
⁴ Department of Pediatrics, University of California, San Diego, 2800 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 2800 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
⁵ Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address: jesper.svejstrup@crick.ac.uk.

Abstract

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amitriptyline / pharmacology
Brain-Derived Neurotrophic Factor / pharmacology
Cell Differentiation / drug effects
Cell Line, Tumor
Chromatin Immunoprecipitation
Cockayne Syndrome / metabolism
Cockayne Syndrome / pathology
DNA Helicases / antagonists & inhibitors
DNA Helicases / genetics
DNA Helicases / metabolism*
DNA Repair Enzymes / antagonists & inhibitors
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism*
Down-Regulation / drug effects
Flavones / pharmacology
Humans
Membrane Glycoproteins / agonists
Membrane Glycoproteins / metabolism
Microscopy, Fluorescence
Poly-ADP-Ribose Binding Proteins
Protein-Tyrosine Kinases / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Real-Time Polymerase Chain Reaction
Receptor, trkB
Synaptotagmins / antagonists & inhibitors
Synaptotagmins / genetics
Synaptotagmins / metabolism

Substances

6,7-dihydroxyflavone
Brain-Derived Neurotrophic Factor
Flavones
Membrane Glycoproteins
Poly-ADP-Ribose Binding Proteins
RNA, Small Interfering
SYT9 protein, human
Synaptotagmins
Amitriptyline
BDNF protein, human
Protein-Tyrosine Kinases
Receptor, trkB
tropomyosin-related kinase-B, human
DNA Helicases
ERCC6 protein, human
DNA Repair Enzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding