title: Glucagon-like peptide-1 protects NSC-34 motor neurons against glucosamine through Epac-mediated glucose uptake enhancement.
abstract: Bioenergetic deficits are considered a common cause of neurodegenerative diseases. Although creatine supplementation has been shown to be effective in certain neurodegenerative disorders, it is less effective in amyotrophic lateral sclerosis, a disease that primarily affects motor neurons. These neurons are particularly vulnerable to a cellular energy deficit. Using the ATP-depleting drug glucosamine, we evaluated whether the incretin hormone glucagon-like peptide (GLP)-1 protects motor neurons against glucosamine-induced cytotoxicity. Undifferentiated NSC-34 cells were differentiated into glutamate-sensitive motor neurons by a modified serum deprivation technique. Glucosamine inhibited the viability of differentiated NSC-34 cells in a time- and dose-dependent manner. Glucosamine also acutely reduced cellular glucose uptake, glucokinase activity and intracellular ATP levels. As a result, the activity of AMP-activated protein kinase as well as endoplasmic reticulum stress increased. Pretreatment with GLP-1 significantly alleviated glucosamine-mediated neurotoxicity by restoring cellular glucose uptake, glucokinase activity and intracellular ATP levels. The protective effect of GLP-1 was replicated by Exendin-4 but not Exendin-9, and not blocked by inhibitors of phosphoinositide-3 kinase, protein kinase A, cSrc, or epidermal growth factor receptor, but it was blocked by an adenylate cyclase inhibitor. A selective activator for exchange proteins directly activated by cAMP (Epac), but not a selective activator for protein kinase A, mimicked the GLP-1 effect. Therefore GLP-1 may exert its effect mainly through cAMP-dependent, Epac-mediated restoration of glucose uptake that is typically impaired by glucosamine. These findings indicate that GLP-1 could be employed therapeutically to protect motor neurons that are susceptible to bioenergetic deficits.
authors.affiliation: Institute for Medical Genetics, Keimyung University School of Medicine, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Jung-Geun
authors.initials: JG
authors.lastname: Lim
authors.forename: Jang-Jun
authors.initials: JJ
authors.lastname: Lee
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Sun-Joo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ho-Chan
authors.initials: HC
authors.lastname: Cho
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Baek
authors.forename: Dae-Kwang
authors.initials: DK
authors.lastname: Kim
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005941:Glucokinase / Q000378:metabolism; D005944:Glucosamine / Q000008:administration & dosage / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006822:Hybrid Cells; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018373:Peripheral Nervous System Agents / Q000008:administration & dosage / Q000633:toxicity*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D018373:Peripheral Nervous System Agents; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005941:Glucokinase; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D005944:Glucosamine