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Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11055-60. doi: 10.1073/pnas.1409314111. Epub 2014 Jul 14.

Absence of lipofuscin in motor neurons of SOD1-linked ALS mice.

Author information

1
Department of Genetics andHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
2
Department of Genetics and.
3
Department of Genetics andHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510 arthur.horwich@yale.edu.

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.

PMID:
25024188
PMCID:
PMC4121794
DOI:
10.1073/pnas.1409314111
[Indexed for MEDLINE]
Free PMC Article

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