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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Substitution
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Autophagy*
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Autophagy-Related Protein-1 Homolog
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Lipofuscin / genetics
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Lipofuscin / metabolism*
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Lysosomes / genetics
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Lysosomes / metabolism*
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Lysosomes / pathology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Transgenic
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Motor Neurons / metabolism*
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Motor Neurons / pathology
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Mutation, Missense
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Sequestosome-1 Protein
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism*
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Superoxide Dismutase-1
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Heat-Shock Proteins
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Lipofuscin
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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Multiprotein Complexes
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SOD1 protein, human
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Autophagy-Related Protein-1 Homolog
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Ulk1 protein, mouse