Материал из hpluswiki
Перейти к навигации Перейти к поиску

Protein CLN8 [C8orf61]


Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis.

Accumulation of autofluorescent storage material in the CNS is a hallmark of neuronal ceroid lipofuscinosis (NCL, Batten disease). Since the retina is generally the first CNS target affected in NCL and could serve as a means to assess early disease progression as well as potential therapeutic responses, we followed the course of postnatal retinal pathology in tissues from the CLN8 (mnd) mouse model of NCL. Cytoplasmic inclusions in the retinal ganglion cell (RGC) layer were shown by periodic acid schiff stain by P7. TUNEL measurements of cell death became significant at P21 (P<0.001) with most cell death occurring in the photoreceptor layer. Significant autofluorescence and RGC hypertrophy were evident in mnd mice at P0, prior to eye opening or significant cell death. An increased understanding of the timing, location, and characteristic retinal pathologies of Batten disease may lead to diagnostic and therapeutic advances in the clinical setting.

MeSH Terms

  • Aging
  • Animals
  • Cell Death
  • Disease Models, Animal
  • Disease Progression
  • Fluorescence
  • Hypertrophy
  • In Situ Nick-End Labeling
  • Inclusion Bodies
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microscopy, Fluorescence
  • Neuronal Ceroid-Lipofuscinoses
  • Retinal Degeneration
  • Retinal Ganglion Cells

A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging.

Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.

MeSH Terms

  • Aging
  • Animals
  • Base Sequence
  • Brain
  • DNA Primers
  • Disease Models, Animal
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neuronal Ceroid-Lipofuscinoses
  • Reverse Transcriptase Polymerase Chain Reaction
  • gamma-Aminobutyric Acid