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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Zhong, Yu³  Mohan, Kabhilan^1,10  Liu, Jinpeng²  Al-Attar, Ahmad⁴  Lin, Penghui⁴  Flight, Robert M.^2,4  Sun, Qiushi^4,11  Warmoes, Marc O.^4,12  Deshpande, Rahul R.⁴  Liu, Huijuan³  Jung, Kyung Sik^1,10  Mitov, Mihail, I^2,13  Lin, Nianwei^9,14  Butterfield, D. Allan^2,5  Lu, Shuyan⁹  Liu, Jinze^2,6,7  Moseley, Hunter N. B.^2,3,7  Fan, Teresa W. M.^2,4,8  Kleinman, Mark E.^1,10  Wang, Qing Jun^1,2 

[1] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40536 USA

[2] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

[4] Univ Kentucky, Ctr Environm & Syst Biochem, Lexington, KY 40536 USA

[5] Univ Kentucky, Dept Chem, Lexington, KY 40536 USA

[6] Univ Kentucky, Dept Comp Sci, Lexington, KY 40536 USA

[7] Univ Kentucky, Inst Biomed Informat, Lexington, KY 40536 USA

[8] Univ Kentucky, Dept Toxicol & Canc Biol, Lexington, KY 40536 USA

[9] Pfizer Inc, San Diego, CA USA

[10] East Tennessee State Univ, Dept Surg, Johnson City, TN USA

[11] Yale Sch Med, Dept Internal Med Endocrinol, New Haven, CT USA

[12] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Belvaux, Luxembourg

[13] Idaho Coll Osteopath Med, Meridian, ID USA

[14] iXCells Biotechnol USA Inc, San Diego, CA USA

关键词: CLN3;    Vision loss;    Retinal pigment epithelium;    Autophagy;    Metabolism;    Glycogen;   

DOI  :  10.1016/j.bbadis.2020.165883

来源: Elsevier

【 摘 要 】

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 nonsyndromic 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 similar to 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.

【 授权许可】

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