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

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Abstract

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
Volume40
Issue number2
DOIs
StatePublished - Nov 2010

Fingerprint

Autophagy
Neurons
Embryonic Structures
Fibroblasts
Mucolipidoses
Achlorhydria
Vision Disorders
Cerebrum
Sirolimus
Ubiquitin
Protease Inhibitors
Knockout Mice
Neurodegenerative Diseases
Cerebral Cortex
Electron Microscopy
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

Curcio-Morelli, C., Charles, F. A., Micsenyi, M. C., Cao, Y., Venugopal, B., Browning, M. F., ... Slaugenhaupt, S. A. (2010). Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiology of Disease, 40(2), 370-377. https://doi.org/10.1016/j.nbd.2010.06.010

Macroautophagy is defective in mucolipin-1-deficient mouse neurons. / Curcio-Morelli, Cyntia; Charles, Florie A.; Micsenyi, Matthew C.; Cao, Yi; Venugopal, Bhuvarahamurthy; Browning, Marsha F.; Dobrenis, Kostantin; Cotman, Susan L.; Walkley, Steven U.; Slaugenhaupt, Susan A.

In: Neurobiology of Disease, Vol. 40, No. 2, 11.2010, p. 370-377.

Research output: Contribution to journalArticle

Curcio-Morelli, C, Charles, FA, Micsenyi, MC, Cao, Y, Venugopal, B, Browning, MF, Dobrenis, K, Cotman, SL, Walkley, SU & Slaugenhaupt, SA 2010, 'Macroautophagy is defective in mucolipin-1-deficient mouse neurons', Neurobiology of Disease, vol. 40, no. 2, pp. 370-377. https://doi.org/10.1016/j.nbd.2010.06.010
Curcio-Morelli C, Charles FA, Micsenyi MC, Cao Y, Venugopal B, Browning MF et al. Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiology of Disease. 2010 Nov;40(2):370-377. https://doi.org/10.1016/j.nbd.2010.06.010
Curcio-Morelli, Cyntia ; Charles, Florie A. ; Micsenyi, Matthew C. ; Cao, Yi ; Venugopal, Bhuvarahamurthy ; Browning, Marsha F. ; Dobrenis, Kostantin ; Cotman, Susan L. ; Walkley, Steven U. ; Slaugenhaupt, Susan A. / Macroautophagy is defective in mucolipin-1-deficient mouse neurons. In: Neurobiology of Disease. 2010 ; Vol. 40, No. 2. pp. 370-377.
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