Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice

Philipp von Eisenhart-Rothe, Alexandra Grubman, Ursula Greferath, Linda J. Fothergill, Andrew I. Jobling, Joanna A. Phipps, Anthony R. White, Erica L. Fletcher, Kirstan A. Vessey

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 Cln6nclf mouse model.

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. Cln6nclf 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: Cln6nclf 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 Cln6nclf 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 Cln6nclf mice at P30.

Original languageEnglish
Pages (from-to)5082-5097
Number of pages16
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number12
DOIs
Publication statusPublished - 1 Oct 2018
Externally publishedYes

Keywords

  • retina
  • photoreceptor
  • rodent
  • autophagy
  • lysosome
  • ceroid-lipofuscinosis neuronal protein 6
  • CLN6
  • neuronal ceroid lipofuscinosis
  • NCI
  • neurodegeneration
  • super-resolution microscopy
  • electroretinogram

Cite this

von Eisenhart-Rothe, Philipp ; Grubman, Alexandra ; Greferath, Ursula ; Fothergill, Linda J. ; Jobling, Andrew I. ; Phipps, Joanna A. ; White, Anthony R. ; Fletcher, Erica L. ; Vessey, Kirstan A. / Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 12. pp. 5082-5097.
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title = "Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice",
abstract = "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 Cln6nclf mouse model.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. Cln6nclf 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: Cln6nclf 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 Cln6nclf 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 Cln6nclf mice at P30.",
keywords = "retina, photoreceptor, rodent, autophagy, lysosome, ceroid-lipofuscinosis neuronal protein 6, CLN6, neuronal ceroid lipofuscinosis, NCI, neurodegeneration, super-resolution microscopy, electroretinogram",
author = "{von Eisenhart-Rothe}, Philipp and Alexandra Grubman and Ursula Greferath and Fothergill, {Linda J.} and Jobling, {Andrew I.} and Phipps, {Joanna A.} and White, {Anthony R.} and Fletcher, {Erica L.} and Vessey, {Kirstan A.}",
year = "2018",
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doi = "10.1167/iovs.18-24757",
language = "English",
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von Eisenhart-Rothe, P, Grubman, A, Greferath, U, Fothergill, LJ, Jobling, AI, Phipps, JA, White, AR, Fletcher, EL & Vessey, KA 2018, 'Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice', Investigative Ophthalmology and Visual Science, vol. 59, no. 12, pp. 5082-5097. https://doi.org/10.1167/iovs.18-24757

Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice. / von Eisenhart-Rothe, Philipp; Grubman, Alexandra; Greferath, Ursula; Fothergill, Linda J.; Jobling, Andrew I.; Phipps, Joanna A.; White, Anthony R.; Fletcher, Erica L.; Vessey, Kirstan A.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 12, 01.10.2018, p. 5082-5097.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf-mice

AU - von Eisenhart-Rothe, Philipp

AU - Grubman, Alexandra

AU - Greferath, Ursula

AU - Fothergill, Linda J.

AU - Jobling, Andrew I.

AU - Phipps, Joanna A.

AU - White, Anthony R.

AU - Fletcher, Erica L.

AU - Vessey, Kirstan A.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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 Cln6nclf mouse model.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. Cln6nclf 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: Cln6nclf 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 Cln6nclf 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 Cln6nclf mice at P30.

AB - 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 Cln6nclf mouse model.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. Cln6nclf 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: Cln6nclf 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 Cln6nclf 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 Cln6nclf mice at P30.

KW - retina

KW - photoreceptor

KW - rodent

KW - autophagy

KW - lysosome

KW - ceroid-lipofuscinosis neuronal protein 6

KW - CLN6

KW - neuronal ceroid lipofuscinosis

KW - NCI

KW - neurodegeneration

KW - super-resolution microscopy

KW - electroretinogram

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U2 - 10.1167/iovs.18-24757

DO - 10.1167/iovs.18-24757

M3 - Article

VL - 59

SP - 5082

EP - 5097

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 1552-5783

IS - 12

ER -