glycogen and Blindness

Juvenile neuronal ceroid lipofuscinosis (JNCL, aka. juvenile Batten disease or CLN3 disease) is a lysosomal storage disease characterized by progressive blindness, seizures, cognitive and motor failures, and premature death. JNCL is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene, whose function is unclear. Although traditionally considered a neurodegenerative disease, CLN3 disease displays eye-specific effects: Vision loss not only is often one of the earliest symptoms of JNCL, but also has been reported in non-syndromic CLN3 disease. Here we described the roles of CLN3 protein in maintaining healthy retinal pigment epithelium (RPE) and normal vision. Using electroretinogram, fundoscopy and microscopy, we showed impaired visual function, retinal autofluorescent lesions, and RPE disintegration and metaplasia/hyperplasia in a Cln3 ~ 1 kb-deletion mouse model [1] on C57BL/6J background. Utilizing a combination of biochemical analyses, RNA-Seq, Seahorse XF bioenergetic analysis, and Stable Isotope Resolved Metabolomics (SIRM), we further demonstrated that loss of CLN3 increased autophagic flux, suppressed mTORC1 and Akt activities, enhanced AMPK activity, and up-regulated gene expression of the autophagy-lysosomal system in RPE-1 cells, suggesting autophagy induction. This CLN3 deficiency induced autophagy induction coincided with decreased mitochondrial oxygen consumption, glycolysis, the tricarboxylic acid (TCA) cycle, and ATP production. We also reported for the first time that loss of CLN3 led to glycogen accumulation despite of impaired glycogen synthesis. Our comprehensive analyses shed light on how loss of CLN3 affect autophagy and metabolism. This work suggests possible links among metabolic impairment, autophagy induction and lysosomal storage, as well as between RPE atrophy/degeneration and vision loss in JNCL.

Topics: Animals; Atrophy; Autophagy; Blindness; Cell Line; Disease Models, Animal; Gene Knock-In Techniques; Gene Knockdown Techniques; Glycogen; Humans; Lysosomes; Membrane Glycoproteins; Mice; Mice, Transgenic; Microscopy, Electron; Molecular Chaperones; Mutation; Neuronal Ceroid-Lipofuscinoses; Retinal Pigment Epithelium; RNA, Small Interfering

The lens nucleus of altricial birds contains a large amount of glycogen. It is not known why glycogen in such concentration does not cause a trace of lens opalescence. Here we report that the altricial pigeon is born with a dense nuclear opacity; this opacity has practically disappeared by 4 weeks of age. Thin-section electron microscopy revealed that the opacity was specifically associated with an enormous number of large glycogen aggregates in nuclear fiber cells. These aggregates of various sizes (up to approximately 5 microns) were composed of smaller individual 35-nm beta glycogen particles. In contrast, glycogen aggregates were not seen in nuclear fiber cells of all transparent older lenses. The glycogen aggregates have gradually dissociated into a homogeneous distribution of individual beta particles in the entire cytoplasm of nuclear fibers which accompanies the development of lens transparency. This study suggests that an extensive accumulation of glycogen aggregates in the lens nucleus is the cause of light scattering and opacification. The transparency of the altricial pigeon lens during normal development is therefore regulated by two different forms of glycogen. Precocial birds such as chick have no lens glycogen, therefore never develop a glycogen cataract and have excellent visual acuity upon hatching.

Topics: Agglutination; Animals; Blindness; Cataract; Columbidae; Glycogen; Lens Nucleus, Crystalline; Microscopy, Electron; Time Factors

Total absence of light or blindness results in atretic changes in the large ovarian follicles. It also caused stromal edema of the uterus and interrupted the estrous cycle. The cells found in the vaginal smear appeared to be that of diestrous. Light deprivation inhibits the synthesis of RNA and protein of the uterus and vagina. Light deprivation of blindness also results in the reduction of the uterine weight and its glycogen content. Antiestrogenic action of light deprivation or removal of the eyes was reflected in a decreased concentration of RNA, protein, sialic acid and glycogen in the uterus and vagina.

Topics: Animals; Blindness; Female; Genitalia, Female; Gerbillinae; Glycogen; Hemoglobins; Light; Organ Size; Proteins; RNA; Sensory Deprivation; Sialic Acids

Topics: Animals; Blindness; Blood Glucose; Carbon Isotopes; Fasting; Glucose; Glucose Tolerance Test; Glycogen; Growth Disorders; Growth Hormone; Insulin; Lipid Metabolism; Male; Rats; Rats, Inbred Strains

Topics: Animals; Blindness; Cell Nucleus; Circadian Rhythm; Glycogen; Histocytochemistry; Lighting; Male; Mice; Pineal Gland

Topics: Age Factors; Animals; Blindness; Female; Glycogen; Histocytochemistry; Light; Lighting; Male; Mice; Pineal Gland; Radiation Effects; Time Factors