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.
Highlights
Neuronal ceroid lipofuscinoses (NCL) are a group of severe neurodegenerative lysosomal storage disorders, and are considered the most common progressive encephalopathies of childhood [1]
The distribution of the autofluorescent lysosomal storage material was evaluated on unstained sections of 54 weeks old nclf mice and age matched control animals by confocal fluorescence microscopy (Figure 1B)
Increased autophagy in the nclf mouse brain Since autophagy has been shown to play a role in the pathogenesis of other forms of NCL, including CLN3 and CLN10 [5,28,29], we investigated whether this lysosomal dysfunction in nclf mice is evident in CLN6 disease
Summary
Neuronal ceroid lipofuscinoses (NCL) are a group of severe neurodegenerative lysosomal storage disorders, and are considered the most common progressive encephalopathies of childhood [1]. The NCLs are caused by mutations in at least nine human CLN genes, which can be linked to the onset and clinical course of the disease [1,2]. The different forms share common clinical features, including progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death [3]. These disorders are characterized by accumulation of autofluorescent ceroid lipopigments in most tissues, but pathological effects are most pronounced in the central nervous system, which displays a progressive and remarkably selective loss of neurons [4,5]. Homozygous nclf mice develop progressive retinal atrophy early in life, show cerebral atrophy, spastic limb paresis at eight months, paralysis and premature death at one year of age
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