title: Absence of lipofuscin in motor neurons of SOD1-linked ALS mice.
abstract: Lipofuscin, or aging pigment, is accreted as red autofluorescence in the lysosomes of motor neuron cell bodies in the ventral horn of WT mice by 3 mo of age. Strikingly, in two presymptomatic ALS mouse strains transgenic for mutant human Cu/Zn superoxide dismutase (SOD1), G85R SOD1YFP and G93A SOD1, little or no lipofuscin was detected in motor neuron cell bodies. Two markers of autophagy, sequestosome 1 (SQSTM1/p62) and microtubule-associated protein 1 light chain 3 (LC3), were examined in the motor neuron cell bodies of G85R SOD1YFP mice and found to be reduced relative to WT SOD1YFP transgenic mice. To elucidate whether the autophagy/lysosome pathway was either impaired or hyperactive in motor neurons, chloroquine was administered to 3-mo-old G85R SOD1YFP mice to block lysosomal hydrolysis. After 2 wk, lipofuscin was now observed in motor neurons, and SQSTM1 and LC3 levels approached those of WT SOD1YFP mice, suggesting that the autophagy/lysosome pathway is hyperactive in motor neurons of SOD1-linked ALS mice. This seems to be mediated at least in part through the mammalian target of rapamycin complex 1 (MTORC1) pathway, because levels of Ser757-phosphorylated Unc-51-like kinase 1 (ULK1), an MTORC1 target, were greatly reduced in the G85R SOD1YFP motor neurons, correspondent to an activated state of ULK1 that initiates autophagy.
authors.affiliation: Department of Genetics andHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Urmi
authors.initials: U
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Genetics andHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Maria
authors.initials: M
authors.lastname: Nagy
authors.affiliation: Department of Genetics and.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Fenton
authors.affiliation: Department of Genetics andHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510 arthur.horwich@yale.edu.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Horwich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008062:Lipofuscin / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D008062:Lipofuscin; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C000606290:SOD1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse