Macroautophagy is defective in mucolipin-1-deficient mouse neurons

Cyntia Curcio-Morelli, Florie A. Charles, Matthew C. Micsenyi, Yi Cao, Bhuvarahamurthy Venugopal, Marsha F. Browning, Kostantin Dobrenis, Susan L. Cotman, Steven U. Walkley, Susan A. Slaugenhaupt

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Mucolipidosis type IV is a neurodegenerative lysosomal disease clinically characterized by psychomotor retardation, visual impairment, and achlorhydria. In this study we report the development of a neuronal cell model generated from cerebrum of Mcoln1-/- embryos. Prior functional characterization of MLIV cells has been limited to fibroblast cultures gleaned from patients. The current availability of the mucolipin-1 knockout mouse model Mcoln1-/- allows the study of mucolipin-1-defective neurons, which is important since the disease is characterized by severe neurological impairment. Electron microscopy studies reveal significant membranous intracytoplasmic storage bodies, which correlate with the storage morphology observed in cerebral cortex of Mcoln1-/- P7 pups and E17 embryos. The Mcoln1-/- neuronal cultures show an increase in size of LysoTracker and Lamp1 positive vesicles. Using this neuronal model system, we show that macroautophagy is defective in mucolipin-1-deficient neurons and that LC3-II levels are significantly elevated. Treatment with rapamycin plus protease inhibitors did not increase levels of LC3-II in Mcoln1-/- neuronal cultures, indicating that the lack of mucolipin-1 affects LC3-II clearance. P62/SQSTM1 and ubiquitin levels were also increased in Mcoln1-/- neuronal cultures, suggesting an accumulation of protein aggregates and a defect in macroautophagy which could help explain the neurodegeneration observed in MLIV. This study describes, for the first time, a defect in macroautophagy in mucolipin-1-deficient neurons, which corroborates recent findings in MLIV fibroblasts and provides new insight into the neuronal pathogenesis of this disease.

Original languageEnglish (US)
Pages (from-to)370-377
Number of pages8
JournalNeurobiology of Disease
Issue number2
StatePublished - Nov 2010


  • Lysosomal disease
  • Macroautophagy
  • Mucolipidosis type IV
  • Mucolipin 1
  • Neuronal storage

ASJC Scopus subject areas

  • Neurology


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