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

Leinonen, Henri; Keksa-Goldsteine, Velta; Ragauskas, Symantas; Kohlmann, Philip; Singh, Yajuvinder; Savchenko, Ekaterina; Puranen, Jooseppi; Malm, Tarja; Kalesnykas, Giedrius; Koistinaho, Jari; Tanila, Heikki; Kanninen, Katja M.

doi:10.1038/s41598-017-01716-1

Cited by 53 publications

(56 citation statements)

References 75 publications

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“…NCL may be caused by disruption of genes encoding lysosomal enzymes (Ppt1 and Cln5) and membrane proteins (Mfsd8) as well as ER membrane (Cln6 and Cln8) and secretory pathway (Grn) proteins, and is characterized by a common lysosomal accumulation of ceroid. Similar to the early retinal phenotype reported for most human NCLs, most mouse models for NCL disease show an early onset of PR degeneration, beginning at 1 month of age and showing greater than 60% degeneration by 6-9 months [253][254][255][256]. Additionally, similar to the adult-onset reported for mutations in human GRN, the mouse model for loss of Grn also shows a late onset PR degeneration by 12 months [257].…”

Section: Category 03: Metabolismmentioning

confidence: 58%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Category 03: Metabolismmentioning

confidence: 58%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…5b) and an increased expression of p62 ( Fig. 5c), suggestive for a block of autophagosome-lysosome maturation 30 . Correspondingly, ultrastructural investigations of patients' fibroblasts in vitro showed increased amounts of both lysosomes and vacuoles containing densely packed, osmiophilic material ( Fig.…”

Section: Relevance To Human Cln5 Diseasementioning

confidence: 89%

Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction

et al. 2020

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CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in Cln5 −/− cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle-specific proteome findings to CLN5 patients' fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment.

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“…14,15 This is also the case for other Cln mutants. 16,17 Alternatively, lysosomal accumulations within the photoreceptors themselves may induce photoreceptor failure and retinal degeneration as has been suggested in the fly. 18 As Cln6 nclf mice are characterized by deposits of lipofuscin in retinal neurons and the RPE, they provide a useful model for identifying which cell type is predominantly responsible for retinal degeneration.…”

mentioning

confidence: 98%

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

Cited by 53 publications

References 75 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction

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

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

Cited by 53 publications

References 75 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction

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

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