Cellular models of Batten disease

Minnis, Christopher J.; Thornton, Christopher D.; FitzPatrick, Lorna M.; McKay, Tristan R.

doi:10.1016/j.bbadis.2019.165559

Cited by 19 publications

(17 citation statements)

References 150 publications

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“…Many animal and mammalian cell models have been used to study the pathological mechanisms underlying the NCLs [7,8]. However, these systems present some limitations, such as the costs associated with maintaining small experimental animals (e.g., mice) and the limited number of phenotypes that can be screened in immortalized or patient-derived human cells.…”

Section: Dictyostelium As a Model Organism For Ncl Researchmentioning

confidence: 99%

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Huber

2020

J Biomed Sci

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The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, belong to a family of neurological disorders that cause blindness, seizures, loss of motor function and cognitive ability, and premature death. There are 13 different subtypes of NCL that are associated with mutations in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14). Similar clinical and pathological profiles of the different NCL subtypes suggest that common disease mechanisms may be involved. As a result, there have been many efforts to determine how NCL proteins are connected at the cellular level. A main driving force for NCL research has been the utilization of mammalian and non-mammalian cellular models to study the mechanisms underlying the disease. One non-mammalian model that has provided significant insight into NCL protein function is the social amoeba Dictyostelium discoideum. Accumulated data from Dictyostelium and mammalian cells show that NCL proteins display similar localizations, have common binding partners, and regulate the expression and activities of one another. In addition, genetic models of NCL display similar phenotypes. This review integrates findings from Dictyostelium and mammalian models of NCL to highlight our understanding of the molecular networking of NCL proteins. The goal here is to help set the stage for future work to reveal the cellular mechanisms underlying the NCLs.

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Section: Dictyostelium As a Model Organism For Ncl Researchmentioning

confidence: 99%

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Huber

2020

J Biomed Sci

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“…Cellular models of NCLs are commonly used to understand cellular biology (Minnis et al., 2019), and as platforms for therapeutic efficacy studies (Gavin et al., 2013; Kim et al., 2012; Linterman et al., 2011). In this study we used mass spectrometry (MS) based secretome profiling to characterise disease specific changes in primary cortical cell cultures of neurons, microglia, and astrocytes derived from the Cln6 nclf mouse.…”

Section: Introductionmentioning

confidence: 99%

An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease

Best

Clare

McDonald

et al. 2021

Journal of Neurochemistry

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Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited childhood neurodegenerative disorders. In addition to the accumulation of auto-fluorescent storage material in lysosomes, NCLs are largely characterised by region-specific neuroinflammation that can predict neuron loss. These phenotypes suggest alterations in the extracellular environment-making the secretome an area of significant interest.This study investigated the secretome in the CLN6 (ceroid-lipofuscinosis neuronal protein 6) variant of NCL. To investigate the CLN6 secretome, we co-cultured neurons and glia isolated from Cln6 nclf or Cln6 ± mice, and utilised mass spectrometry to compare protein constituents of conditioned media. The significant changes noted in cathepsin enzymes, were investigated further via western blotting and enzyme activity assays. Viral-mediated gene therapy was used to try and rescue the wildtype phenotype and restore the secretome-both in vitro in co-cultures and in vivo in mouse plasma. In Cln6 nclf cells, proteomics revealed a marked increase in catabolic and cytoskeletal-associated proteins-revealing new similarities between the pathogenic signatures of NCLs with other neurodegenerative disorders. These changes were, in part, corrected by gene therapy intervention, suggesting these proteins as candidate in vitro biomarkers. Importantly, these in vitro changes show promise for in vivo translation, with Cathepsin L (CTSL) activity reduced in both co-cultures and Cln6 nclf plasma samples post gene-therapy. This work suggests the secretome plays a role in CLN6 pathogenesis and highlights its potential use as an in vitro model. Proteomic changes present a list of candidate biomarkers for monitoring disease and assessing potential therapeutics in future studies.

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“…Yeast provide useful model systems for many human diseases due their genetic tractability. We have developed yeast models to understand the neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, a group of rare childhood inherited neurodegenerative disorders 1 . Most are inherited in an autosomal recessive manner, with mutations in 13 known human genes 2 , some of which are conserved in yeast.…”

Section: Introductionmentioning

confidence: 99%

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

Minnis

Townsend

Petschnigg

et al. 2021

Sci Rep

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Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102–208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype–phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.

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Cellular models of Batten disease

Cited by 19 publications

References 150 publications

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

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