A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

Tang, Cynthia; Han, Jimin; Dalvi, Sonal; Manian, Kannan Vrindavan; Winschel, Lauren; Volland, Stefanie; Soto, Celia; Galloway, Chad A.; Spencer, Whitney; Roll, Michael; Milliner, Caroline; Bonilha, Vera L.; Johnson, Tyler B.; Latchney, Lisa R.; Weimer, Jill M.; Augustine, Erika F.; Mink, Jonathan W.; Gullapalli, Vamsi K.; Chung, Mina; Williams, David S.; Singh, Ruchira

doi:10.1038/s42003-021-01682-5

Cited by 25 publications

(35 citation statements)

References 91 publications

(108 reference statements)

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“…Based on these findings, it might be reasonable to assume that the lysosome regulator PGRN is highly expressed in the RPE layer and may play a central role in the regulation of intercellular digestion of RPE. However, few studies have focused on the morphological and functional changes in RPE in CLN models [ 38 ]. Thus, future studies are needed to elucidate the exact functions of PGRN in RPE cells.…”

Section: Discussionmentioning

confidence: 99%

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

Takahashi

Nakamura

Shimazawa

et al. 2021

IJMS

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Progranulin (PGRN) is a secreted glycoprotein that regulates numerous cellular processes. The role of PGRN as a regulator of lysosomes has recently received attention. The purpose of this study was to characterize the retinal phenotype in mature PGRN knockout (Grn−/−) mice. The a-wave amplitude of scotopic electroretinogram and outer nuclear thickness were significantly reduced at 6 months of age in Grn−/− mice compared to wild-type (Grn+/+) mice. In Grn−/− mice, retinal microglial cells accumulated on the retinal pigment epithelium (RPE) apical layer, and the number of infiltrated microglia and white fundus lesions between 2 and 6 months of age showed a close affinity. In Grn+/+ mice, PGRN was located in the retina, while the strongest PGRN signals were detected in the RPE-choroid. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid were demonstrated. Our data suggest that the subretinal translocation of microglia is a characteristic phenotype in the retina of mature PGRN knockout mice. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid might modulate microglial dynamics in PGRN knockout mice.

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Section: Discussionmentioning

confidence: 99%

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

Takahashi

Nakamura

Shimazawa

et al. 2021

IJMS

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“…Neuronal ceroid lipofuscinoses (NCL), also referred to as Batten disease, are a collection of neurodegenerative lysosomal storage disorders characterized by an overaccumulation of lipofuscin, a fluorescent mixture of partially digested proteins and lipids, that progressively builds up with age in the lysosomes of various cell types, including neurons (Adler et al 2015 ; Tang et al 2021 ). Most neurodegenerative diseases tend to be present in adults and develop with advancing senility.…”

Section: Neurodegenerative Diseases: the Big Picturementioning

confidence: 99%

CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics

Sen

Thummer

2022

Neurotox Res

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Neurodegenerative diseases are prominent causes of pain, suffering, and death worldwide. Traditional approaches modelling neurodegenerative diseases are deficient, and therefore, improved strategies that effectively recapitulate the pathophysiological conditions of neurodegenerative diseases are the need of the hour. The generation of human-induced pluripotent stem cells (iPSCs) has transformed our ability to model neurodegenerative diseases in vitro and provide an unlimited source of cells (including desired neuronal cell types) for cell replacement therapy. Recently, CRISPR/Cas9-based genome editing has also been gaining popularity because of the flexibility they provide to generate and ablate disease phenotypes. In addition, the recent advancements in CRISPR/Cas9 technology enables researchers to seamlessly target and introduce precise modifications in the genomic DNA of different human cell lines, including iPSCs. CRISPR-iPSC-based disease modelling, therefore, allows scientists to recapitulate the pathological aspects of most neurodegenerative processes and investigate the role of pathological gene variants in healthy non-patient cell lines. This review outlines how iPSCs, CRISPR/Cas9, and CRISPR-iPSC-based approaches accelerate research on neurodegenerative diseases and take us closer to a cure for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and so forth.

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“…More recently, a study aimed to understand the role of CLN3 in retinal pigment epithelium (RPE) structure and function by generating iPSC-RPE cells from fibroblasts of CLN3 disease patients has implicated the contribution of the CLN3 gene in RPE dysfunction and photoreceptor outer segment (POS) phagocytosis in CLN3 disease [ 107 ]. The CLN3 iPSC-RPE cells showed an affected structure and function in a cell autonomous manner when compared to control; moreover, the RPE structure necessary for POS phagocytosis was also abnormal and decreased apical RPE microvilli density, and reduced POS binding was also observed which resulted in the lower uptake of POS by CLN3 iPSC-RPE cells.…”

Section: Ipsc-based Phenotypic Modeling For Drug Discovery In the Nclsmentioning

confidence: 99%

“…Consistent with the impaired lysosomal degradation of POS by RPE cells in CLN3 disease pathology [ 111 ], CLN3 in iPSC-RPE cells was colocalized with the lysosomal marker LAMP1. This study, therefore, suggested that RPE cells may be a crucial gene therapy target to combat the loss of vision phenotype in CLN3 disease [ 107 ].…”

Section: Ipsc-based Phenotypic Modeling For Drug Discovery In the Nclsmentioning

confidence: 99%

Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

2021

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Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

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A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

Cited by 25 publications

References 91 publications

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics

Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

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