Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

Yi Cao, Janice A. Espinola, Elisa Fossale, Ashish C. Massey, Ana Maria Cuervo, Marcy E. MacDonald, Susan L. Cotman

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3 Δex7/8 knock-in mice and CbCln3Δex7/8 cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wild-type cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.

Original languageEnglish (US)
Pages (from-to)20483-20493
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number29
DOIs
StatePublished - Jul 21 2006

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Autophagy
Lysosome-Associated Membrane Glycoproteins
Vacuoles
Cell death
Sirolimus
Coloring Agents
Aging of materials
Chemical activation
Cells
Feedback
Mitochondrial Turnover
Genetic Models
Lysosomes
Organelles
Proteins
Cell Survival
Cell Death
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., & Cotman, S. L. (2006). Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. Journal of Biological Chemistry, 281(29), 20483-20493. https://doi.org/10.1074/jbc.M602180200

Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. / Cao, Yi; Espinola, Janice A.; Fossale, Elisa; Massey, Ashish C.; Cuervo, Ana Maria; MacDonald, Marcy E.; Cotman, Susan L.

In: Journal of Biological Chemistry, Vol. 281, No. 29, 21.07.2006, p. 20483-20493.

Research output: Contribution to journalArticle

Cao, Y, Espinola, JA, Fossale, E, Massey, AC, Cuervo, AM, MacDonald, ME & Cotman, SL 2006, 'Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis', Journal of Biological Chemistry, vol. 281, no. 29, pp. 20483-20493. https://doi.org/10.1074/jbc.M602180200
Cao, Yi ; Espinola, Janice A. ; Fossale, Elisa ; Massey, Ashish C. ; Cuervo, Ana Maria ; MacDonald, Marcy E. ; Cotman, Susan L. / Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 29. pp. 20483-20493.
@article{210f02ce66b54bfd88c823b2589ccbe3,
title = "Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis",
abstract = "Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3 Δex7/8 knock-in mice and CbCln3Δex7/8 cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wild-type cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.",
author = "Yi Cao and Espinola, {Janice A.} and Elisa Fossale and Massey, {Ashish C.} and Cuervo, {Ana Maria} and MacDonald, {Marcy E.} and Cotman, {Susan L.}",
year = "2006",
month = "7",
day = "21",
doi = "10.1074/jbc.M602180200",
language = "English (US)",
volume = "281",
pages = "20483--20493",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "29",

}

TY - JOUR

T1 - Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

AU - Cao, Yi

AU - Espinola, Janice A.

AU - Fossale, Elisa

AU - Massey, Ashish C.

AU - Cuervo, Ana Maria

AU - MacDonald, Marcy E.

AU - Cotman, Susan L.

PY - 2006/7/21

Y1 - 2006/7/21

N2 - Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3 Δex7/8 knock-in mice and CbCln3Δex7/8 cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wild-type cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.

AB - Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3 Δex7/8 knock-in mice and CbCln3Δex7/8 cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wild-type cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.

UR - http://www.scopus.com/inward/record.url?scp=33745976466&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745976466&partnerID=8YFLogxK

U2 - 10.1074/jbc.M602180200

DO - 10.1074/jbc.M602180200

M3 - Article

VL - 281

SP - 20483

EP - 20493

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 29

ER -