Cell cycle arrest in Batten disease lymphoblast cells

Kang, Sunyang; Kim, June-Bum; Heo, Tae‐Hwe; Kim, Sung-Jo

doi:10.1016/j.gene.2013.02.022

Cited by 12 publications

(3 citation statements)

References 37 publications

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“…However, chemokines have not been studied in great detail in a healthy brain or in Batten disease, and the extent to which they may play a part in neurodegeneration remains unclear. Additionally, females are more vulnerable than males to develop Alzheimer’s disease, and although androgens have been studied less extensively than estrogens, androgens exert anti-inflammatory effects on microglia in AD models [39, 40].…”

Section: Discussionmentioning

confidence: 99%

Tracking sex-dependent differences in a mouse model of CLN6-Batten disease

Poppens

Cain

Johnson

et al. 2019

Orphanet J Rare Dis

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BackgroundCLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression.ResultsA number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females.ConclusionsThus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies.Electronic supplementary materialThe online version of this article (10.1186/s13023-019-0994-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Tracking sex-dependent differences in a mouse model of CLN6-Batten disease

Poppens

Cain

Johnson

et al. 2019

Orphanet J Rare Dis

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“…8 Studies have linked the protein to intracellular trafficking, autophagy, apoptosis, lysosomal pH homeostasis, cell cycle control, osmoregulation, and calcium homeostasis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] However, the precise function of CLN3 is still not known. As a result, there are currently no effective treatments for the disease.…”

Section: Introductionmentioning

confidence: 99%

Aberrant adhesion impacts early development in aDictyosteliummodel for juvenile neuronal ceroid lipofuscinosis

Huber

Myre

Cotman

2016

Cell Adhesion & Migration

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Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, refers to a group of severe neurodegenerative disorders that primarily affect children. The most common subtype of the disease is caused by loss-of-function mutations in CLN3, which is conserved across model species from yeast to human. The precise function of the CLN3 protein is not known, which has made targeted therapy development challenging. In the social amoeba Dictyostelium discoideum, loss of Cln3 causes aberrant mid-to-late stage multicellular development. In this study, we show that Cln3-deficiency causes aberrant adhesion and aggregation during the early stages of Dictyostelium development. cln3 cells form ∼30% more multicellular aggregates that are comparatively smaller than those formed by wild-type cells. Loss of Cln3 delays aggregation, but has no significant effect on cell speed or cAMP-mediated chemotaxis. The aberrant aggregation of cln3 cells cannot be corrected by manually pulsing cells with cAMP. Moreover, there are no significant differences between wild-type and cln3 cells in the expression of genes linked to cAMP chemotaxis (e.g., adenylyl cyclase, acaA; the cAMP receptor, carA; cAMP phosphodiesterase, pdsA; g-protein α 9 subunit, gpaI). However, during this time in development, cln3 cells show reduced cell-substrate and cell-cell adhesion, which correlate with changes in the levels of the cell adhesion proteins CadA and CsaA. Specifically, loss of Cln3 decreases the intracellular level of CsaA and increases the amount of soluble CadA in conditioned media. Together, these results suggest that the aberrant aggregation of cln3 cells is due to reduced adhesion during the early stages of development. Revealing the molecular basis underlying this phenotype may provide fresh new insight into CLN3 function.

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“…Acid sphingomyelinase-derived ceramide specifically binds to and activates CTSD [Heinrich at al., 1999]. Several reports have related impaired CLN3 expression to the accumulation of ceramide [Kang et al, 2013; Makoukji et al, 2015; Rusyn et al, 2008]. Rusyn et al reported that wild type CLN3, but not mutant CLN3, binds galactosylceramide, and suggested that CLN3 may function as a galactosylceramide transporter [Rusyn et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

Role of the Lysosomal Membrane Protein, CLN3, in the Regulation of Cathepsin D Activity

Carcel-Trullols

Kovács

Pearce

2017

J of Cellular Biochemistry

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Among Neuronal Ceroid Lipofuscinoses (NCLs), which are childhood fatal neurodegenerative disorders, the juvenile onset form (JNCL) is the most common. JNCL is caused by recessive mutations in the CLN3 gene. CLN3 encodes a lysosomal/endosomal transmembrane protein but its precise function is not completely known. We have previously reported that in baby hamster kidney (BHK) cells stably expressing myc-tagged human CLN3 (myc-CLN3), hyperosmotic conditions drastically increased myc-CLN3 mRNA and protein expression. In the present study, we analyzed the consequences of hyperosmolarity and increased CLN3 expression on cathepsin D activity and prosaposin processing using BHK cells transiently or stably expressing myc-CLN3. We found that hyperosmolarity increased lysotracker staining of lysosomes and elevated the levels of myc-CLN3 and lysosome-associated membrane protein-1 (LAMP1). Hyperosmolarity, independently of the expression level of myc-CLN3, decreased the levels of prosaposin and saposin D, which are protein cofactors in sphingolipid metabolism. The lysosomal enzyme cathepsin D (CTSD) mediates the proteolytic cleavage of prosaposin precursor into saposins A–D. Myc-CLN3 colocalized with CTSD and activity of CTSD decreased as myc-CLN3 expression increased and clearly decreased under hyperosmotic conditions. Nevertheless, levels of CTSD measured by Western blotting were not altered under any studied condition. Our results suggest a direct involvement of CLN3 in the regulation of CTSD activity.

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Cell cycle arrest in Batten disease lymphoblast cells

Cited by 12 publications

References 37 publications

Tracking sex-dependent differences in a mouse model of CLN6-Batten disease

Tracking sex-dependent differences in a mouse model of CLN6-Batten disease

Aberrant adhesion impacts early development in aDictyosteliummodel for juvenile neuronal ceroid lipofuscinosis

Role of the Lysosomal Membrane Protein, CLN3, in the Regulation of Cathepsin D Activity

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