title: Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma.
abstract: BACKGROUND
  Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases.
  
  
  RESULTS
  Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa (-/-) mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture.
  
  
  CONCLUSIONS
  This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Pete A
authors.initials: PA
authors.lastname: Williams
authors.affiliation: School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Tribble
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Keating W
authors.initials: KW
authors.lastname: Pepper
authors.affiliation: School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Cross
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Morgan
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA. simon.john@jax.org.|Department of Ophthalmology, Tufts University of Medicine, Boston, MA, 02111, USA. simon.john@jax.org.|The Howard Hughes Medical Institute, Bar Harbor, ME, 04609, USA. simon.john@jax.org.
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA. gareth.howell@Jax.org.|Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, Boston, MA, USA. gareth.howell@Jax.org.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Howell
mesh_terms: D000818:Animals; D015922:Complement C1q / Q000235:genetics*; D003712:Dendrites / Q000378:metabolism*; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism*; D051379:Mice; D051381:Rats; D012165:Retinal Ganglion Cells / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*
chemical_list: D015922:Complement C1q
keywords: C1; C1qa; Complement; Dendrite; Glaucoma; Retinal ganglion cell; Synapse