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Apoptotic photoreceptor loss and altered expression of lysosomal proteins in the nclf mouse model of neuronal ceroid lipofuscinosis.

Abstract：

PURPOSE:Mutations in the CLN6 gene cause variant late-infantile neuronal ceroid lipofuscinosis, a lysosomal storage disorder clinically characterized by progressive loss of vision, dementia, seizures, and early death. Here, we analyzed the time course of photoreceptor loss and the role of lysosomes in nclf mice, an animal model of the human CLN6 disease. METHODS:Labeling of apoptotic cells, activated astrocytes, and Müller cells, and expression analyses of glial fibrillary acidic protein, rhodopsin, and lysosomal proteins were performed on nclf mice during the course of retinal degeneration. In addition, the distribution and variability of storage material was examined at the ultrastructural level. RESULTS:Progressive apoptotic loss of photoreceptor cells was observed in nclf mice, resulting in reduction of the outer nuclear layer to approximately 3 rows of photoreceptor cells at 9 months of age. Onset of reactive gliosis was observed in 1-month-old nclf mice. Ultrastructural analysis revealed lysosomal storage material containing curvilinear and fingerprint-like inclusions in various retinal cell types. Expression levels of soluble mannose 6-phosphate-containing lysosomal enzymes, such as cathepsin D and the lysosomal membrane protein Lamp1, were increased in retinal cells of nclf mice. CONCLUSIONS:Accumulation of heterogeneous nondegraded macromolecules in dysfunctional lysosomes and autolysosomes impairs photoreceptor cells, ultimately leading to early-onset apoptotic death with subsequent activation of astrocytes and Müller cells in the retina of nclf mice. The defined steps of photoreceptor degeneration suggest that nclf mice might serve as an ideal animal model for experimental therapeutic approaches aimed at attenuating vision loss in neuronal ceroid lipofuscinosis.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Bartsch U,Galliciotti G,Jofre GF,Jankowiak W,Hagel C,Braulke T

doi

10.1167/iovs.13-12945

subject

Has Abstract

pub_date

2013-10-23 00:00:00

pages

6952-9

issue

eissn

0146-0404

issn

1552-5783

pii

iovs.13-12945

journal_volume

pub_type

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Apoptotic photoreceptor loss and altered expression of lysosomal proteins in the nclf mouse model of neuronal ceroid lipofuscinosis.