title: Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.
authors.affiliation: Ph.D. Program for Aging, China Medical University, Taichung, Taiwan, ROC; Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40447, Taiwan, ROC.
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Hsueh
authors.affiliation: Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC.
authors.forename: Tzyy-Wen
authors.initials: TW
authors.lastname: Chiou
authors.affiliation: Graduate Institute of Microbiology and Public Health, National Chung Hsing University, Taichung, Taiwan, ROC.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Chiang
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.
authors.forename: Cesar V
authors.initials: CV
authors.lastname: Borlongan
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.affiliation: Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Angela Yu Hsuan
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40447, Taiwan, ROC; Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC. Electronic address: shinnzong@yahoo.com.tw.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC; Department of Medicine, China Medical University, Taichung, Taiwan, ROC. Electronic address: duke_harn@yahoo.com.tw.
authors.forename: Horng-Jyh
authors.initials: HJ
authors.lastname: Harn
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D010796:Phthalic Anhydrides / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D015996:Survival Rate / Q000639:trends
chemical_list: D010796:Phthalic Anhydrides; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1; C026105:butylidenephthalide