Disruption of the Autophagy-Lysosome Pathway Is Involved in Neuropathology of the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis
Open Access
- 20 April 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (4), e35493
- https://doi.org/10.1371/journal.pone.0035493
Abstract
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.This publication has 49 references indexed in Scilit:
- Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid LipofuscinosisAmerican Journal of Human Genetics, 2011
- Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6American Journal of Human Genetics, 2011
- Autophagy and the ubiquitin-proteasome system: Collaborators in neuroprotectionBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2008
- Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosisNeurobiology of Disease, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- Dissecting the ER-Associated Degradation of a Misfolded Polytopic Membrane ProteinCell, 2008
- ER chaperones in mammalian development and human diseasesFEBS Letters, 2007
- Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosisNeurobiology of Disease, 2007
- Suppression of basal autophagy in neural cells causes neurodegenerative disease in miceNature, 2006
- Loss of autophagy in the central nervous system causes neurodegeneration in miceNature, 2006