Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak, Wanda; Brandenstein, Laura; Dulz, Simon; Hagel, Christian; Storch, Stephan; Bartsch, Udo

doi:10.1167/iovs.16-20158

Cited by 26 publications

(27 citation statements)

References 50 publications

(95 reference statements)

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“…This is followed by loss of rod photoreceptor nuclei, whereas cones, inner retinal neurons and photopic vision seem to be relatively long preserved. Correspondingly, preferential loss of signal from rods over cones has been detected in South Hampshire sheep, Tibetan Terrier dogs, PON dogs and CLN7 mouse model of NCLs 21, 51, 52 , well as in patients with juvenile type of NCLs 4, 53 .…”

Section: Discussionmentioning

confidence: 78%

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Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Leinonen

Keksa-Goldsteine

Ragauskas

et al. 2017

Sci Rep

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The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5 disease) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases. Vision loss is among the first clinical signs in childhood forms of NCLs. Mutations in CLN5 underlie CLN5 disease. The aim of this study was to characterize how the lack of normal functionality of the CLN5 protein affects the mouse retina. Scotopic electroretinography (ERG) showed a diminished c-wave amplitude in the CLN5 deficient mice already at 1 month of age, indicative of pathological events in the retinal pigmented epithelium. A- and b-waves showed progressive impairment later from 2 and 3 months of age onwards, respectively. Structural and immunohistochemical (IHC) analyses showed preferential damage of photoreceptors, accumulation of autofluorescent storage material, apoptosis of photoreceptors, and strong inflammation in the CLN5 deficient mice retinas. Increased levels of autophagy-associated proteins Beclin-1 and P62, and increased LC3b-II/LC3b-I ratio, were detected by Western blotting from whole retinal extracts. Photopic ERG, visual evoked potentials, IHC and cell counting indicated relatively long surviving cone photoreceptors compared to rods. In conclusion, CLN5 deficient mice develop early vision loss that reflects the condition reported in clinical childhood forms of NCLs. The vision loss in CLN5 deficient mice is primarily caused by photoreceptor degeneration.

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Section: Discussionmentioning

confidence: 78%

“…In addition to the CLN5 mouse model, findings from several other animal models of NCLs imply a similar pattern of pathological events in the retina 12, 21, 51, 52 . We speculate that the retinopathy in several forms of NCLs may be caused by failure of lysosomes to degrade phagosomes and autophagosomes.…”

Section: Discussionmentioning

confidence: 89%

Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Leinonen

Keksa-Goldsteine

Ragauskas

et al. 2017

Sci Rep

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“…The consequences of MFSD8 mutation may be synaptic dysfunction resulting in disordered neurotransmitter release and local excitotoxicity. This may lead to downstream secondary consequences that have been described such as the accumulation of aggregate storage material in neuronal cells, 5,16,31,32 impaired autophagy, 33 and cell death, as well as accompanying inflammation that occurs both in the brains of MFSD8-deficient patients 31 and in the MFSD8-knockout dog 34 and mouse models. 33,35 All previously published MFSD8 mutation combinations associated with disease are listed at http://www.ucl.ac.uk/ncl/ and Alexa Fluor 568-conjugated secondary antibody (red) or Alexa Fluor 488-conjugated secondary antibody (green) and DAPI nuclear counterstain (blue) are shown.…”

Section: Figurementioning

confidence: 99%

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

Khan¹,

El‐Asrag

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Khan KN, El-Asrag ME, Ku CA, et al.; for NIHR BioResource-Rare Diseases and UK Inherited Retinal Disease Consortium. Specific alleles of CLN7/ MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy. Invest Ophthalmol Vis Sci. 2017;58:290658: -291458: . DOI:10.1167 PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS.Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS.Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b-to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses.CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

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“…Early retinal pathology is common to all forms of NCL and is exhibited by a CLN7 mutant mouse (Jankowiak et al, 2016). It is interesting, therefore, that CLN7 is expressed in the developing visual system of Drosophila larvae, both in the imaginal eye discs that give rise to structures of the eye and in the optic lobes of the CNS into which the photoreceptors project (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Atrophy of the visual system is a common feature of all of the childhood-onset forms of NCL and is seen in CLN7 mutant mice (Jankowiak et al, 2016); again, this may reflect a conserved ancestral role for CLN7 and it will be interesting to determine whether CLN7 mutant flies suffer similar visual pathology.…”

Section: Discussionmentioning

confidence: 99%

in vivo localization of the neuronal ceroid lipofuscinosis proteins, CLN3 and CLN7 , at endogenous expression levels

Mohammed

O'Hare

Warley

et al. 2017

Neurobiology of Disease

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The neuronal ceroid lipofuscinoses are a group of recessively inherited, childhood-onset neurodegenerative conditions. Several forms are caused by mutations in genes encoding putative lysosomal membrane proteins. Studies of the cell biology underpinning these disorders are hampered by the poor antigenicity of the membrane proteins, which makes visualization of the endogenous proteins difficult. We have used Drosophila to generate knock-in YFP-fusions for two of the NCL membrane proteins: CLN7 and CLN3. The YFP-fusions are expressed at endogenous levels and the proteins can be visualized live without the need for overexpression. Unexpectedly, both CLN7 and CLN3 have restricted expression in the CNS of Drosophila larva and are predominantly expressed in the glia that form the insect blood-brain-barrier. CLN7 is also expressed in neurons in the developing visual system. Analogous with murine CLN3, Drosophila CLN3 is strongly expressed in the excretory and osmoregulatory Malpighian tubules, but the knock-in also reveals unexpected localization of the protein to the apical domain adjacent to the lumen. In addition, some CLN3 protein in the tubules is localized within mitochondria. Our in vivo imaging of CLN7 and CLN3 suggests new possibilities for function and promotes new ideas about the cell biology of the NCLs.

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Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Cited by 26 publications

References 50 publications

Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

in vivo localization of the neuronal ceroid lipofuscinosis proteins, CLN3 and CLN7 , at endogenous expression levels

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