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 CLN6nclf 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 Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6nclf retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6nclf 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 CLN6nclf 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 CLN6nclf 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 CLN6nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.
Highlights
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive neurodegenerative lysosomal storage disorders with a frequency of 7–8 in 100,000 live births worldwide [1,2]
To characterize the temporal retinal degeneration and glial activation in CLN6nclf mice we studied animals at different ages ranging from one to eight months
At eight months of age, the photoreceptor cell layer in particular was severely compromised in CLN6nclf retinas with only a few rows of cell nuclei remaining (Fig. 1A)
Summary
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive neurodegenerative lysosomal storage disorders with a frequency of 7–8 in 100,000 live births worldwide [1,2]. A general hallmark of all NCL subtypes is the accumulation of autofluorescent material in neurons causing progressive degeneration and tissue atrophy [6] This results in clinically common features shared by all NCL disorders, including visual impairment, mental and motor deficits, spontaneous seizures and premature death [7]. Glial activation has been described in the brain of a CLN6nclf sheep model [14] as well as other NCL models [15], indicating that inflammation and glial processes are another hallmark of NCL. It is currently unknown whether the modulation of microglial response can affect disease progression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
