Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice

Hafler, Brian P.; Klein, Zoe A.; Zhou, Zhishang; Strittmatter, Stephen M.

doi:10.1016/j.brainres.2014.09.023

Cited by 32 publications

(40 citation statements)

References 32 publications

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“…We reported retinal degeneration accompanied by electrophysiological dysfunction in Grn knockout mice (13), which was subsequently reported by others (14). Similar to findings in cortical neurons from Grn knockout mice and in various NCL animal models (7), we observed NCL-like lysosomal storage material in retinal neurons from Grn knockout mice (Fig.…”

Section: Resultssupporting

confidence: 70%

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

et al. 2017

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Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

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Section: Resultssupporting

confidence: 70%

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

et al. 2017

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“…Loss of rod photoreceptors in Cln7 KO mice was evident long before damage and loss of neurons in the brain became detectable, 36 and thus represents the earliest phenotypic manifestation of CLN7 deficiency in the central nervous system. Progressive degeneration of photoreceptor cells has also been observed in mouse models of various other lysosomal storage diseases, such as mucolipidosis (ML) II, 47 ML IV, 48 arylsulfatase G-deficiency, 43 CLC7-deficiency, 49 and several NCL variants, including CLN6, 29 CLN8, 28 CLN10, 30 and CLN11 disease, 31 indicating that photoreceptor cells are particularly vulnerable to lysosomal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neuronal ceroid lipofuscinoses comprise a genetically heterogeneous group of mainly childhood-onset neurodegenerative lysosomal storage disorders. Progressive loss of vision is among the typical clinical symptoms of these fatal disorders. Here, we performed a detailed analysis of retinal degeneration in mice deficient in the lysosomal membrane protein CLN7, a novel animal model of CLN7 disease.METHODS. Immunohistochemical analyses of retinas at different ages were performed to qualitatively and quantitatively characterize retinal degeneration in CLN7-deficient mice. Storage material in mutant retinas was analyzed by electron microscopy, and expression levels of various lysosomal proteins were studied using immunohistochemistry, immunoblot analyses, and quantitative real-time PCR.RESULTS. We observed an early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice, resulting in the loss of more than 70% rod photoreceptors in 4-month-old animals. The number of cone photoreceptors was not detectably altered at this age. Loss of rod photoreceptors was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas. We also found a marked dysregulation of various lysosomal proteins in mutant retinas. CONCLUSIONS.We conclude that the retina of CLN7-deficient mice represents a useful model to elucidate the pathomechanisms ultimately leading to neurodegeneration in CLN7 disease, and to evaluate the efficacy of strategies aimed at developing treatments for this fatal neurodegenerative lysosomal storage disorder.

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“…Although PGRN null ( Grn −/−) mice recapitulate some of pathological features of FTLD such as microgliosis and retinal degeneration, Grn heterozygous ( Grn +/−) mice do not, and both fail to show TDP-43-positive inclusions, a key pathological hallmark of FTLD. Therefore, Grn −/− mice have been studied as the best available mouse model for human PGRN haploinsufficiency-related FTLD [42,1,61,80,27,78,29,47,53]. Given this evidence, although GRN rs5848 T allele causes 10–20% reduction of PGRN in humans and GRN mutation carriers with AD clinical presentation are all heterozygotes, we utilize Grn −/− as well as Grn +/− mice.…”

Section: Introductionmentioning

confidence: 99%

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

et al. 2017

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Progranulin (PGRN) is implicated in Alzheimer’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer’s disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

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Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice

Cited by 32 publications

References 32 publications

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

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