Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3Δex7/8-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

Finn, Rozzy; Kovács, Attila; Pearce, David A.

doi:10.1016/j.neuint.2011.02.003

Cited by 36 publications

(43 citation statements)

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“…While its exact cellular function remains unknown, CLN3 belongs to the major facilitator superfamily of membrane transporters and has been implicated in the transport of protons, amino acids, neurotransmitters, and proteins in lysosomes, [52][53][54][55][56][57] at the Golgi, 58 and across synapses. 59,60 Electron microscopy studies localizes CLN3 in the retina to photoreceptor inner segments, inner retinal cells, and Muller glia. 61 Mouse and in vitro studies have implicated CLN3 in trafficking and stability of the inner-segment protein Na + /K + -ATPase.…”

Section: 27mentioning

confidence: 99%

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Hull

Arno

et al. 2017

JAMA Ophthalmol

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IMPORTANCE Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.OBJECTIVE To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTSA multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURESLongitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.RESULTS There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.CONCLUSIONS AND RELEVANCE This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

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Section: 27mentioning

confidence: 99%

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Hull

Arno

et al. 2017

JAMA Ophthalmol

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“…1A). The surface cross-linking method has successfully been used to study AMPA receptor surface expression in different brain regions[4, 5, 10, 13, 14, 17, 30]. …”

Section: Resultsmentioning

confidence: 99%

“…Surface cross-linking in acutely isolated brain slices was carried out as we previously described [13, 14]. …”

Section: Methodsmentioning

confidence: 99%

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Abnormally increased surface expression of AMPA receptors in the cerebellum, cortex and striatum of Cln3 mice

Kovács

Hof

Pearce

2015

Neuroscience Letters

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Mutations in the CLN3 gene cause a fatal neurodegenerative disorder, juvenile CLN3 disease. Exploring the cause of the motor coordination deficit in the Cln3−/− mouse model of the disease we have previously found that attenuation of AMPA receptor activity in 1-month-old Cln3−/− mice significantly improves their motor coordination [20]. To elucidate the mechanism of the abnormally increased AMPA receptor function in Cln3−/− mice, we examined the surface expression of AMPA receptors using surface cross-linking in brain slices from 1-month-old wild type (WT) and Cln3−/− mice. In surface cross-linked brain samples, Western blotting for AMPA receptor subunits revealed significantly increased surface levels of GluA1 and GluA2 in the cerebellum, and of GluA2 in the cortex and striatum of Cln3−/− mice as compared to WT mice. Expression levels of the GluA4 subunit were similar in the cerebellum of WT and Cln3−/− mice. While intracellular GluA1 levels in the WT and Cln3−/− cerebellum or cortex were similar, the intracellular expression of GluA1 in the Cln3−/− striatum was decreased to 56% of the WT level. Our results show a prominent increase in AMPA receptor surface expression in the brain of Cln3−/− mice and suggest that CLN3 is involved in the regulation of AMPA receptor surface expression.

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“…Primary cultures of cerebellar granule neurons were prepared from seven-day-old WT and Ppt1 −/− mouse pups as previously described (12, 14, 15). Briefly, meninges were removed from cerebella and the tissue was minced with a tissue chopper (McIlwain Tissue Chopper, Brinkmann).…”

Section: Methodsmentioning

confidence: 99%

Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia

2016

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Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-transpyrrolidine-2,4-dicarboxylic acid) or Zn2+-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1−/− cultures. Ppt1−/− neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP+ (1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.

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Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3Δex7/8-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

Cited by 36 publications

References 34 publications

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Abnormally increased surface expression of AMPA receptors in the cerebellum, cortex and striatum of Cln3 mice

Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia

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