title: Fibrates inhibit the apoptosis of Batten disease lymphoblast cells via autophagy recovery and regulation of mitochondrial membrane potential.
abstract: Batten disease (BD; also known as juvenile neuronal ceroid lipofuscinosis) is a genetic disorder inherited as an autosomal recessive trait and is characterized by blindness, seizures, cognitive decline, and early death resulting from the inherited mutation of the CLN3 gene. Mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, disrupted autophagy, and enhanced apoptosis have been suggested to play a role in BD pathogenesis. Fibrates, a class of lipid-lowering drugs that induce peroxisome proliferator-activated receptor-α (PPAR-α) activation, are the most commonly used PPAR agonists. Assuming that fibrates have a neuroprotective effect, we studied the effects of fibrates, fenofibrate, bezafibrate, and gemfibrozil on apoptosis, depolarization of mitochondrial membrane, and defective autophagy in BD lymphoblast cells. The viability of fibrate-treated BD lymphoblast cells increased to levels of normal lymphoblast cells. In addition, treatment with fibrates inhibited depolarization of mitochondrial membrane potential in BD lymphoblast cells. Defective autophagy in BD lymphoblast cells was normalized when treated with fibrates as indicated by increased acridine orange staining. The recovery of autophagy in BD lymphoblast cells is most likely attributed to the upregulation of autophagy proteins, lysosomal-associated membrane protein 1 (LAMP1), and LC3 I/II, after treatment with fibrates. This study therefore suggests that fibrates may have a therapeutic potential against BD.
authors.affiliation: Department of Biotechnology, Hoseo University, 165, Baebang, Asan, Chungnam, 31499, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Animal Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Song
authors.affiliation: Department of Animal Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Hak-Kyo
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, College of Biomedical Sciences, Soonchunhyang University, Asan, 336-745, Republic of Korea.
authors.forename: SunShin
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Life Science and Biotechnology, Soonchunhyang University, Asan, 336-745, Republic of Korea.
authors.forename: Yong Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Lab of Immunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea.
authors.forename: Tae-Hwe
authors.initials: TH
authors.lastname: Heo
authors.affiliation: Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong, 339-700, Republic of Korea. toddjun@korea.ac.kr.
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.affiliation: Department of Biotechnology, Hoseo University, 165, Baebang, Asan, Chungnam, 31499, Republic of Korea. sungjo@hoseo.edu.
authors.forename: Sung-Jo
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001629:Bezafibrate / Q000494:pharmacology*; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology*; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D047493:PPAR alpha / Q000819:agonists
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D047493:PPAR alpha; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate
keywords: Autophagy; Batten disease; Lymphoblast; Mitochondria; PPAR-α