Abstract
SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA damage, suggesting that the observed differences are unlikely to be the result of aberrant neuronal activity. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.
Competing Interest Statement
Although not related to the present study, SG is a shareholder of Muna Therapeutics and Teitur Trophics, both involved in developing therapies directed at SorCS2. The remaining authors declare that they have no competing interests.
Footnotes
Katerina O. Gospodinova: kgospodi{at}exseed.ed.ac.uk ; Ditte Olsen: olsen{at}biomed.au.dk; Mathias Kaas mko{at}biomed.au.dk; Susan M. Anderson S.M.Anderson{at}ed.ac.uk; Jonathan Phillips Jonathan.Phillips{at}ed.ac.uk; Rosie M. Walker: rwalke13{at}staffmail.ed.ac.uk; Mairead L. Bermingham: mairead.bermingham{at}ed.ac.uk; Abigail L. Payne: abbiepayne22{at}hotmail.com; Panagiotis Giannopoulos: s1582089{at}ed.ac.uk; Divya Pandya: divyapandya{at}hotmail.co.uk; Tara L. Spires-Jones: tara.spires-jones{at}ed.ac.uk; Catherine M. Abbott: c.abbott{at}ed.ac.uk; David J. Porteous: david.porteous{at}ed.ac.uk; Simon Glerup: glerup{at}biomed.au.dk; Kathryn L. Evans: Kathy.Evans{at}ed.ac.uk
Abbreviations
- 53BP1
- p53-binding protein 1
- ADHD
- Attention deficit hyperactivity disorder
- ALS
- Amyotrophic lateral sclerosis
- BDNF
- Brain-derived neurotrophic factor
- BSA
- Bovine serum albumin
- Ct
- Cycle threshold
- DEXA
- Dexamethasone
- DG
- Dentate gyrus
- DSB
- Double-strand break
- EV
- Empty vector
- FACS
- Fluorescence-activated cell sorting
- GDNF
- Glial cell-derived neurotrophic factor
- gRNA
- Guide RNA
- GWAS
- Genome-wide association study
- hnRNP-U
- Heterogeneous nuclear ribonucleoprotein U
- KCl
- Potassium chloride
- KO
- Knock-out
- LTD
- Long-term depression
- LTP
- Long-term potentiation
- LUHMES
- Lund human mesencephalic
- MSN
- Medium spiny neurons
- NHEJ
- Non-homologous end joining
- NMDAR
- N-methyl-D-aspartate receptor
- PBS
- Phosphate-buffered saline
- PLO
- Poly-L-Ornithine
- PSD
- Post-synaptic density
- PTZ
- Pentylenetetrazol
- ROS
- Reactive oxygen species
- SNP
- Single-nucleotide polymorphism
- TBS
- Tris-Buffered Saline
- TDP-43
- Transactivation response DNA-binding protein of 43kDa
- TH+
- Tyrosine hydroxylase-positive
- TopoIIβ
- Topoisomerase IIβ
- TrkB
- Tropomyosin receptor kinase B
- Vps10p
- Vacuolar protein sorting (VPS) 10p
- VTA
- Ventral tegmental area
- WT
- Wild-type