Abnormalities in cellular adhesion of neuroblastoma and fibroblast models of Lesch Nyhan syndrome

Stacey, N C; Ma, Muñoz-Fernández; Duley, JA; Connolly, G.P.

doi:10.1016/s0306-4522(00)00149-4

Cited by 12 publications

(5 citation statements)

References 28 publications

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“…LRRK2 has previously been shown to interact with members of the Rho family [ 21 , 22 ] and has a potential role in actin cytoskeleton dynamics. The fibroblast adhesion test has earlier been used in two other neurological disorders, in Alzheimer disease and in Lesch Nyham disease, and in both studies cellular adhesion properties of patient fibroblasts were altered, being decreased and increased respectively [ 39 , 40 ]. In our study we detected no alteration in the adhesion of fibroblasts from Parkinson patients carrying LRRK2 mutations in the kinase domain or in the ROC domain compared to fibroblasts from healthy controls carrying wild type LRRK2.…”

Section: Discussionmentioning

confidence: 99%

No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts

et al. 2015

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Mutations within the LRRK2 gene have been identified in Parkinson’s disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion.

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Section: Discussionmentioning

confidence: 99%

No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts

et al. 2015

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“…However, the mechanism by which features of LNS result from impaired purine metabolism is still not well understood. It was also documented that adhesion of HGprt-deficient neuroblastoma as well as fibroblasts from patients with LNS exhibited dramatically enhanced adhesion compared to control cells (114) and could have consequences for the maturation of the central nervous system, as seen in the smaller brain size of LNS and LNVs children (115)(116)(117). It was also reported that HGprt-deficiency was accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the AD/presenilin signaling pathways (118).…”

Section: Epigenetic Regulation Of App Regulation Of Alternative App Pmentioning

confidence: 94%

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Nguyen¹

2015

Biomolecular Concepts

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Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age < 65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age > 65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APPmRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

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“…- adhesion of HGprt-deficient neuroblastomas as well fibroblasts from patients with LND/LNVs exhibited dramatically enhanced adhesion compared to control [119] , and could have consequences for the maturation of the central nervous system, as seen in the small brain size of LND/LNVs children [120] – [122] ;…”

Section: Discussionmentioning

confidence: 99%

Encephalomalacia/gliosis, deep venous thrombosis, and cancer in Arg393His antithrombin Hanoi and the potential impact of the β-amyloid precursor protein (APP) on thrombosis and cancer

Nguyen

2022

AIMSN

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<abstract> <p>A heterozygous Arg393His point mutation at the reactive site of antithrombin (AT) gene causing thrombosis in a Vietnamese patient is reported and named as Arg393His in AT-Hanoi. The present variant is characterized by a severe reduction of functionally active AT plasma concentration to 42% of normal resulting in multiple severe thrombotic events such as cerebral venous thrombosis (CVT) (encephalomalacia/gliosis), recurrent deep venous thrombosis (DVT) and the development of kidney cancer. Today the complexity of thrombophilia has grown with appreciation that multiple inherited and acquired risk factors may interact to result in a clinically thrombotic phenotype. This article focuses on the following issues: (1) pathophysiology and clinical conditions of Arg393His in AT-Hanoi; (2) “two way association” between cancer and thrombosis in which venous thromboembolism (VTE) can be both a presenting sign and a complication of cancer; (3) efficacy of anticoagulants used for the prevention of cancer-related thrombosis; (4) conditions of acquired risk factors such as cancer or genetic disorders via epigenetic modifications in gene-gene (epistasis) and/or gene-environment interactions such as in Lesch-Nyhan disease (LND), in which the β-amyloid precursor protein (APP) that may interact to predispose a patient to thrombosis and cancer. It is also necessary to study the hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme, AT, and APP using expression vectors for exploring their impact on LND, thrombosis as well as other human diseases, especially the ones related to APP such as Alzheimer's disease (AD) and cancer. For such a purpose, the construction of expression vectors for HGprt and APP, with or without the glycosyl-phosphatidylinositol (GPI) anchor, was performed as described in Ref. #148 (Nguyen, K. V., Naviaux, R. K., Nyhan, W. L. Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). <italic>Nucleosides Nucleotides Nucleic Acids</italic> 2020, 39: 905–922). In the same manner, the construction of expression vectors for AT and APP can be performed as shown in <xref ref-type="fig" rid="neurosci-09-02-010-g006">Figure 6</xref>. These expressions vectors, with or without GPI anchor, could be used as tools for (a) studying the effects of Arg393His mutation in AT; (b) studying the emerging role of Arg393His mutation in AT and cancer; (c) studying intermolecular interactions between APP and AT.</p> <p>Furthermore, the construction of expression vectors as described in Ref. #148, especially the one with GPI, can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) <xref ref-type="bibr" rid="b155">[155]</xref>,<xref ref-type="bibr" rid="b156">[156]</xref>, for example).</p> </abstract>

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Abnormalities in cellular adhesion of neuroblastoma and fibroblast models of Lesch Nyhan syndrome

Cited by 12 publications

References 28 publications

No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts

No Dopamine Cell Loss or Changes in Cytoskeleton Function in Transgenic Mice Expressing Physiological Levels of Wild Type or G2019S Mutant LRRK2 and in Human Fibroblasts

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Encephalomalacia/gliosis, deep venous thrombosis, and cancer in Arg393His antithrombin Hanoi and the potential impact of the β-amyloid precursor protein (APP) on thrombosis and cancer

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