Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage

Abstract

Juvenile neuronal ceroid lipofuscinosis (jNCL) is a rare but fatal inherited lysosomal storage disorder mainly affecting children. The disease is caused by mutations in the CLN3 gene that lead to the accumulation of storage material in many tissues, prominent immune responses and neuronal degeneration. One of the first symptoms is vision loss followed by motor dysfunction and mental decline. The established Cln3Δex7/8 mouse model mimics many pathological features of the human disease except the retinal phenotype, which is very mild and occurs only very late in these mice. Here, we first carefully analyzed the retinal structure and microglia responses in these animals. While prominent autofluorescent spots were present in the fundus, only a moderate reduction of retinal thickness and no prominent microgliosis was seen in young CLN3-deficient mice. We next genetically introduced a light-sensitive RPE65 variant and established a light-damage paradigm that showed a high susceptibility of young Cln3Δex7/8 mice after exposure to 10,000 lux bright light for 30 min. Under these ‘low light’ conditions, CLN3-deficient mice showed a strong retinal degeneration, microglial activation, deposition of autofluorescent material and transcriptomic changes compared to wild-type animals. Finally, we treated the light-exposed Cln3Δex7/8 animals with the immunomodulatory compound minocycline, and thereby rescued the retinal phenotype and diminished microgliosis. Our findings indicate that exposure to specific light conditions accelerates CLN3-dependent retinal degeneration, and that immunomodulation by minocycline could be a possible treatment option to delay vision loss in jNCL patients..

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

“…A critical role of inflammatory immune responses in the progression of retinal dystrophies in NCL has also been demonstrated in mouse models of CLN1, CLN3 and CLN6 disease. Attenuation of the retinal pathology in these animal models was observed upon treatment with various immunomodulatory compounds, such as fingolimod, teriflunomide, minocyclin, curcumin or docosahexaenoic acid, and in genetic models with a compromised immune system [ 44 , 45 , 46 , 47 , 48 ].…”

Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon inCLN6

“…It has been hypothesized that NCL-associated neuroinflammation contributes to the disease pathogenesis ( Qiao et al 2007 ; Groh et al 2013 ; Kay and Palmer 2013 ; Xiong and Kielian 2013 ; Groh et al 2017 ). However, anti-inflammatory drug treatments targeted to the CNS have produced variable results in attenuating NCL disease progression ( Seehafer et al 2011 ; Kay and Palmer 2013 ; Augustine and Mink 2016 ; Groh et al 2017 ; Dannhausen et al 2018 ). Developing a better understanding of the molecular mechanisms that underlie neuroinflammation associated with the NCLs will facilitate development of rational approaches to better targeted anti-inflammatory treatments that can be tested in animal models such as the CLN6 cat.…”

Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype

“…Whether the degeneration of other retinal cell types affected in the PPT1-deficient retina was also attenuated by these treatments was, however, not analysed in these studies. Early-onset microgliosis has recently also been reported to closely accompany light-induced retinal degeneration in the Cln3 Δex7/8 mouse model of CLN3 disease 56 and the progressive loss of photoreceptor cells in the nclf mouse model of CLN6 disease 57 . Interestingly, treatment of Cln3 Δex7/8 mice with the immunomodulatory compound minocycline or of nclf mice with the immunomodulatory compounds curcumin or docosahexaenoic acid resulted in attenuation of microgliosis and partial correction of the retina pathology 56,57 .…”