Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease)

Ouseph, Madhu M.; Kleinman, Mark E.; Wang, Qing Jun

doi:10.1111/nyas.12990

Cited by 31 publications

(34 citation statements)

References 119 publications

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“…Patients with CLN3 disease experience early vision loss because of atrophy of retinal pigment macular epithelium (in 63% of patients) (Ouseph et al . ). Based on the importance of whiskers for object identification and navigation, the whisker atrophy in Cln3 Δex7/8 mice suggests an intriguing functional parallel with visual loss in CLN3 patients, although this remains highly speculative.…”

Section: Discussionmentioning

confidence: 97%

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

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Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 microglia are primed toward a pro-inflammatory phenotype typified by exaggerated caspase 1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3 mouse brain. Based on the ability of caspase 1 to cleave a large number of substrates that have been implicated in JNCL pathology, we examined the functional implications of caspase 1 inflammasome activity by crossing Cln3 and caspase 1-deficient mice to create Cln3 /Casp-1 animals. Caspase 1 deletion influenced motor behavior deficits and astrocyte activation in the context of CLN3 mutation, since both were significantly reversed in Cln3 /Casp-1 mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 mice that was partially caspase 1-dependent. However, not all CLN3 phenotypes were reversed following caspase 1 deletion, since no significant differences in lysosomal accumulation or microglial activation were observed between Cln3 and Cln3 /Casp-1 mice. Although the molecular targets of aberrant caspase 1 activity in the context of CLN3 mutation remain to be identified, our studies suggest that caspase 1 may represent a potential therapeutic target to mitigate some attributes of CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".

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Section: Discussionmentioning

confidence: 97%

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

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“…Decline in vision caused by retinal accumulation of lipofuscin and photoreceptor death represents one of the first symptoms in infantile and childhood NCL forms. 2,30 In the Cln6 nclf mouse model of late-infantile NCL there was a significant loss of rod photoreceptor function at P18, prior to photoreceptor nuclei loss at P60. In contrast, postphotoreceptor rod and cone pathway function were not affected until P120 and P240, respectively.…”

Section: Discussionmentioning

confidence: 99%

Failure of Autophagy–Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed inCln6^nclfMice

Eisenhart-Rothe

Grubman

Greferath

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Vision loss caused by photoreceptor death represents one of the first symptoms in neuronal ceroid lipofuscinosis, a condition characterized by accumulation of intracellular waste. Cln6 nclf mice have a naturally occurring mutation in ceroid-lipofuscinosis neuronal (CLN) protein 6 and are a model of this disorder. In order to identify the effect intracellular waste (lipofuscin) accumulation plays in driving retinal degeneration, the time course of degeneration was carefully characterized functionally using the electroretinogram and structurally using histology. METHODS. Cln6 nclf and C57BL/6J, wild-type, mice were studied at postnatal day 18 (P18), P30, P60, P120, and P240, and retinal degeneration was correlated with changes in the retinal pigment epithelial (RPE) and neuronal autophagy-lysosomal pathways using super-resolution microscopy. RESULTS. In Cln6 nclf mice there was significant loss of rod photoreceptor function at P18, prior to photoreceptor nuclei loss at P60. In contrast, cone pathway function was not affected until P240. The loss of rod photoreceptor function correlated with significant disruption of the autophagy-lysosomal degradation pathways within photoreceptors, but not in the RPE or other retinal neurons. Additionally, there was cytosolic accumulation of P62 and undigested mitochondrial-derived, ATP synthase subunit C in the photoreceptor layers of Cln6 nclf mice at P30. CONCLUSIONS. These results suggest that rod photoreceptors have an increased sensitivity to disturbances in the autophagy-lysosomal pathway and the subsequent failure of mitochondrial turnover, relative to other retinal cells. It is likely that primary failure of the rod photoreceptors rather than the RPE or other retinal neurons underlies the early visual dysfunction that occurs in the Cln6 nclf mouse model.

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“…In addition, there is atrophy of the nerve-fiber layer and ganglion cells and significant gliosis of the optic nerve. 11 Autofluorescent cytoplasmic ceroid granules accumulate predominantly in the photoreceptor-cell layer and in the retinal ganglion cells. Autofluorescence is prominent in the epithelial cells of the conjunctiva and ciliary body as well, but not in the cornea.…”

Section: Human Pathologymentioning

confidence: 99%

Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights

Østergaard

2016

DNND

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The present review is focused on juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) due to a mutation in CLN3. Functional vision impairment occurring around 5–6 years of age is the first symptom in more than 80% of patients. Approximately 2 years later (though sometimes simultaneously), obvious signs of cognitive impairment appear. Behavior problems can occur in advance, especially in boys. These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms. Following the teens, severe dementia is present, including loss of memory, attention, and general reasoning abilities, as well as loss of independent adaptive skills such as mobility, feeding, and communicating. Sleep abnormalities, such as settling problems, nocturnal awakenings, and nightmares, are reported in more than half of patients. The vast majority, if not all, patients develop seizures, starting at approximately 10 years of age. Generalized tonic–clonic seizure occurs as the only type of seizure in approximately half of patients, and in combination with partial seizures in a third of patients. There seems to be no difference in seizure severity according to sex or genotype, and there is great variation in seizure activity among patients. Soon after diagnosis, patients begin to have slight ataxic symptoms, and at adolescence extrapyramidal symptoms (rigidity, bradykinesia, slow steps with flexion in hips and knees) occur with increasing frequency. Chewing and swallowing difficulties emerge as well, and food intake is hampered in the late teens. Disabling periodically involuntary movements may occur as well. A progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus-node dysfunction, ultimately leading to severe bradycardia and/or other conduction abnormalities, starts in the mid-teens. Patients are usually bedridden at 20 years of age, and death usually occurs in the third decade of life.

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Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease)

Cited by 31 publications

References 119 publications

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Failure of Autophagy–Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed inCln6^nclfMice

Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights

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Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease)

Cited by 31 publications

References 119 publications

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Failure of Autophagy–Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed inCln6nclfMice

Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights

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Failure of Autophagy–Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed inCln6^nclfMice