Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium.

Autor: Zhong Y; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States., Mohan K; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, United States., Liu J; Markey Cancer Center, University of Kentucky, Lexington, KY, United States., Al-Attar A; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Lin P; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Flight RM; Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Sun Q; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Warmoes MO; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Deshpande RR; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States., Liu H; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States., Jung KS; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, United States., Mitov MI; Markey Cancer Center, University of Kentucky, Lexington, KY, United States., Lin N; Pfizer Inc., San Diego, CA, United States., Butterfield DA; Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Department of Chemistry, University of Kentucky, Lexington, KY, United States., Lu S; Pfizer Inc., San Diego, CA, United States., Liu J; Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Department of Computer Science, University of Kentucky, Lexington, KY, United States; Institute for Biomedical Informatics, University of Kentucky, Lexington, KY, United States., Moseley HNB; Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States; Institute for Biomedical Informatics, University of Kentucky, Lexington, KY, United States., Fan TWM; Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY, United States; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States., Kleinman ME; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, United States., Wang QJ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, United States; Markey Cancer Center, University of Kentucky, Lexington, KY, United States. Electronic address: qingjun.wang@uky.edu.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2020 Oct 01; Vol. 1866 (10), pp. 165883. Date of Electronic Publication: 2020 Jun 25.
DOI: 10.1016/j.bbadis.2020.165883
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: