title: Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7.
abstract: OBJECTIVE
  Neuronal ceroid lipofuscinoses comprise a genetically heterogeneous group of mainly childhood-onset neurodegenerative lysosomal storage disorders. Progressive loss of vision is among the typical clinical symptoms of these fatal disorders. Here, we performed a detailed analysis of retinal degeneration in mice deficient in the lysosomal membrane protein CLN7, a novel animal model of CLN7 disease.
  
  
  METHODS
  Immunohistochemical analyses of retinas at different ages were performed to qualitatively and quantitatively characterize retinal degeneration in CLN7-deficient mice. Storage material in mutant retinas was analyzed by electron microscopy, and expression levels of various lysosomal proteins were studied using immunohistochemistry, immunoblot analyses, and quantitative real-time PCR.
  
  
  RESULTS
  We observed an early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice, resulting in the loss of more than 70% rod photoreceptors in 4-month-old animals. The number of cone photoreceptors was not detectably altered at this age. Loss of rod photoreceptors was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas. We also found a marked dysregulation of various lysosomal proteins in mutant retinas.
  
  
  CONCLUSIONS
  We conclude that the retina of CLN7-deficient mice represents a useful model to elucidate the pathomechanisms ultimately leading to neurodegeneration in CLN7 disease, and to evaluate the efficacy of strategies aimed at developing treatments for this fatal neurodegenerative lysosomal storage disorder.
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Wanda
authors.initials: W
authors.lastname: Jankowiak
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Brandenstein
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Dulz
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Storch
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Bartsch