Disease relevance of Cln3

• Since retinal degeneration is an early consequence of Batten disease, we examined the eyes of Cln3 knockout mice (1-20 months of age), along with heterozygotes and appropriate controls, to determine whether or not the Cln3 defect would lead to characteristic retinal degeneration and visual loss [1].
• The absence of Cln3 causes loss of axons, axonal hypertrophy, and a reduction in myelination of retinal ganglion cells [2].
• Mortality after generalized seizure was high in both Cln3-/- and wt animals at late neonatal and immature developmental stages [3].

High impact information on Cln3

• Instead, Cln3( Deltaex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex and cerebellum, as well as neurological deficits and premature death [4].
• Moreover, Cln3( Deltaex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations [4].
• We tested the fine epitope specificity of F28C4 by using alanine-substituted peptide analogues and found that residues critical for TCR recognition, Cln3 and Pro6, are also necessary for F28C4 recognition [5].
• Accumulation of autofluorescent material and intracellular inclusions were markedly increased in Cln3 knockout retinal ganglion cells, as well as most other nuclear layers [1].
• Apoptosis was observed in the photoreceptor layer of Cln3 knockout [1].

Biological context of Cln3

• In summary, it appears that accumulation of autofluorescent material, carbohydrate storage material, as well as apoptotic cell death are retinal manifestations of the Cln3 defect that do not appear to extinguish retinal function in this mouse model of Batten disease [1].
• METHODS: High-density oligonucleotide arrays were used to profile approximately 19,000 mRNAs in the eye of 10-week-old Cln3-knockout and normal mice, and the data were compared with that for the cerebellum in the same model as a means to identify gene expression changes that are specific to the eye [6].
• Having previously demonstrated that Cln3(-/-) mice have decreased optic nerve axonal density, we now demonstrate a decrease in nerve conduction [7].
• METHODS: Using flurothyl gas inhalation, we examined seizure-induction latencies in Cln3-/- mice and wildtype (wt) controls at time points that represent late neonatal, immature, mature, and aged time points [3].
• An apparent shift in metabolism toward gluconeogenesis is also evident in Cln3-knockout mice [8].

Anatomical context of Cln3

• Nerve fiber density was also significantly decreased in Cln3 knockout retinae [1].
• To explore this issue we undertook detailed morphological characterization of the Cln3 null mutant (Cln3(-/-)) mouse model of juvenile NCL (JNCL) that revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread loss of hippocampal interneurons that was first evident at 14 months of age [9].
• In addition, it was also elucidated that the amino terminal region of Cln3p faces the cytosol [10].
• CONCLUSIONS: These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function [11].

Associations of Cln3 with chemical compounds

• Retinal pathology and function in a Cln3 knockout mouse model of juvenile Neuronal Ceroid Lipofuscinosis (batten disease) [1].

Analytical, diagnostic and therapeutic context of Cln3

• Western blot analysis demonstrated that Cln3 was expressed in retinas and optic nerves of mouse and primate [2].
• Furthermore, 18 genes were identified and 6 validated by semiquantitative RT-PCR that have altered expression in the eye, but not in the cerebellum of Cln3-knockout mice [6].

References