Correction: Progressive Retinal Degeneration and Glial Activation in the CLN6^nclfMouse Model of Neuronal Ceroid Lipofuscinosis: A Beneficial Effect of DHA and Curcumin Supplementation

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6 nclf mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Mu ¨ller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6 nclf retina co-inciding with reactive Mu ¨ller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6 nclf retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA), could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6 nclf mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6 nclf retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6 nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.

X-ray fluorescence microscopic measurement of elemental distribution in the mouse retina with age

“…The thickness of the photoreceptor cell layer (ONL) was greatly reduced by 57% in 8-month old Cln6 mutants (our unpublished data), consistent with previous reports. 11,15 Curiously, elemental concentrations of Zn and Ca were not altered in Cln6-mice in any region of the retina or RPE or at any age tested, unlike the change in distribution of these elements in the Cln6 nclf cerebellar neurons (Fig. 5A and B).…”

“…The naturally occurring Cln6 nclf mutant mice develop aggressive retinal degeneration from 1 month of age and accumulate retinal and RPE lipofuscin. 11 We recently identified disrupted metal metabolism in these animals, and demonstrated loss of the zinc transporter, Zip7, as an early event in the brains of CLN6 mutant sheep and Cln6 nclf mouse cortical and cerebellar neurons. [12][13][14] In addition, our previous work demonstrated subcellular Zn and calcium (Ca) mishandling in Cln6 nclf cerebellar cells by X-ray fluorescence microscopy (XFM) high-resolution elemental mapping and partial restoration of this phenotype via treatment with a Zn delivery complex.…”

“…[12][13][14] In addition, our previous work demonstrated subcellular Zn and calcium (Ca) mishandling in Cln6 nclf cerebellar cells by X-ray fluorescence microscopy (XFM) high-resolution elemental mapping and partial restoration of this phenotype via treatment with a Zn delivery complex. 12 Cln6 nclf mice lose retinal function and exhibit photoreceptor loss and lipofuscin accumulation, 11,15 thus we sought to determine whether metal dyshomeostasis is evident in the retina in this aggressive genetic model of blindness and whether biometal changes in the eye underlie photoreceptor loss in this model.…”

Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

“…This has necessitated a detailed examination of the visual pathway, which has shown marked retinal degeneration in these patients [ 13 , 69 , 70 ]. In many forms of NCL, based on animal models, it is also often accompanied by optic nerve degeneration [ 5 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. Furthermore, mouse models have been shown to exhibit significant pathology in central visual pathways within the dorsolateral geniculate nucleus of the thalamus and visual cortex in many forms of NCL [ 42 , 60 , 61 , 62 ], and it is likely that other retinal receptive nuclei are also affected.…”

Experimental Therapeutic Approaches for the Treatment of Retinal Pathology in Neuronal Ceroid Lipofuscinoses

“…Treatment of the mutant mice with the antibiotic and anti-inflammatory drug minocycline prior to light stress led to reduced photoreceptor loss and decreased amounts of autofluorescent storage material ( 56 ). Based on the strong reactive gliosis present in Cln6 nclf retinas, mutant mice were treated with the natural immunomodulators curcumin and docosahexanoic acid [DHA, ( 57 )]. In the curcumin- and DHA-treated Cln6 nclf mice, reactive gliosis was attenuated and the decline in visual acuity and ERG amplitudes was delayed when compared with untreated mutant mice.…”