Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis.
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Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis. / Thelen, Melanie; Damme, Markus; Daμμe, Markus; Schweizer, Michaela; Hagel, Christian; Wong, Andrew M S; Cooper, Jonathan D; Braulke, Thomas; Galliciotti, Giovanna.
In: PLOS ONE, Vol. 7, No. 4, 4, 2012, p. 35493.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis.
AU - Thelen, Melanie
AU - Damme, Markus
AU - Daμμe, Markus
AU - Schweizer, Michaela
AU - Hagel, Christian
AU - Wong, Andrew M S
AU - Cooper, Jonathan D
AU - Braulke, Thomas
AU - Galliciotti, Giovanna
PY - 2012
Y1 - 2012
N2 - Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age-dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration.
AB - Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age-dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration.
KW - Animals
KW - Disease Models, Animal
KW - Mice
KW - Atrophy
KW - Proteasome Endopeptidase Complex/metabolism
KW - Mutagenesis, Insertional
KW - Transcription Factors/metabolism
KW - Proteolysis
KW - Lysosomes/metabolism
KW - Autophagy
KW - Recombinant Fusion Proteins/metabolism
KW - Membrane Proteins/genetics/metabolism
KW - Green Fluorescent Proteins/metabolism
KW - Astrocytes/metabolism/physiology
KW - Cerebellum/metabolism/pathology
KW - Endoplasmic Reticulum Stress
KW - Hippocampus/metabolism/pathology
KW - Neuronal Ceroid-Lipofuscinoses/metabolism/pathology/physiopathology
KW - Olfactory Bulb/pathology
KW - Ubiquitinated Proteins/metabolism
KW - Unfolded Protein Response
KW - Animals
KW - Disease Models, Animal
KW - Mice
KW - Atrophy
KW - Proteasome Endopeptidase Complex/metabolism
KW - Mutagenesis, Insertional
KW - Transcription Factors/metabolism
KW - Proteolysis
KW - Lysosomes/metabolism
KW - Autophagy
KW - Recombinant Fusion Proteins/metabolism
KW - Membrane Proteins/genetics/metabolism
KW - Green Fluorescent Proteins/metabolism
KW - Astrocytes/metabolism/physiology
KW - Cerebellum/metabolism/pathology
KW - Endoplasmic Reticulum Stress
KW - Hippocampus/metabolism/pathology
KW - Neuronal Ceroid-Lipofuscinoses/metabolism/pathology/physiopathology
KW - Olfactory Bulb/pathology
KW - Ubiquitinated Proteins/metabolism
KW - Unfolded Protein Response
U2 - 10.1371/journal.pone.0035493
DO - 10.1371/journal.pone.0035493
M3 - SCORING: Journal article
VL - 7
SP - 35493
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
M1 - 4
ER -
