Fibroblast models of neurological disorders: fluorescence measurement studies

Connolly, G.P.

doi:10.1016/s0165-6147(98)01202-4

Cited by 65 publications

(32 citation statements)

References 29 publications

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“…Studies on fibroblasts from patients with neurological disorders have been previously carried out and revealed a wealth of information on how such disorders occur (48,49). Our data provide the evidence that fibroblasts are a good and easy peripheral source for studying molecular basis of AD, including early events taking place before the onset of the disease.…”

Section: Discussionmentioning

confidence: 59%

Up-regulation of Glycohydrolases in Alzheimer's Disease Fibroblasts Correlates with Ras Activation

Emiliani

Urbanelli

Racanicchi

et al. 2003

Journal of Biological Chemistry

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The lysosomal system is up-regulated in the brain of patients with Alzheimer's Disease (AD), as demonstrated by previous experiments carried out in postmortem samples of brain patients. In this paper we provide evidence that an up-regulation of lysosomal glycohydrolases (␣-D-mannosidase, ␤-D-hexosaminidase, and ␤-D-galactosidase) takes place in skin fibroblasts from AD patients affected either by sporadic or familial forms and is detectable also in presymptomatic subjects carrying the above mutations but healthy at the time of skin biopsy. This increase of enzyme activity is consequent to a transcriptional up-regulation. The oncogene Ras appears to be involved in the regulation of enzymatic activity. A parallel increase of Ras transcript and Ras protein, without an increase of p44/p42 MAPK activation was revealed in the same AD fibroblasts. An activation of p38 MAPK already described to occur in neurodegenerative diseases such as Alzheimer's, was also found in fibroblasts derived from AD patients. High levels of expression of the constitutively active form of Ras in normal or AD fibroblasts induced glycohydrolases up-regulation. Overall results demonstrated that glycohydrolases up-regulation, as well as Ras up-regulation, are early markers of AD, detectable at peripheral level, and good candidates to be exploited for diagnostic purposes. These data also provide the first proof for a role of Ras in regulating lysosomal glycohydrolases expression.

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Section: Discussionmentioning

confidence: 59%

Up-regulation of Glycohydrolases in Alzheimer's Disease Fibroblasts Correlates with Ras Activation

Emiliani

Urbanelli

Racanicchi

et al. 2003

Journal of Biological Chemistry

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“…Here, we examined gene-expression profiles in fibroblasts from humans and two species of African great apes, bonobos, and gorillas. Cultured fibroblasts are frequently used to study properties of connective tissue, inherited metabolic diseases, and cellular aging (Connolly 1998;Cristofalo et al 1998;Zamir and Geiger 2001). The substantial number of fibroblast cell lines from donors of known age and gender allows us to evaluate and correct for intraspecies variation that mask or falsely indicate the presence of differentially expressed genes.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Gene-Expression Patterns in Human and African Great Ape Cultured Fibroblasts

Karaman

Houck²,

Chemnick³

et al. 2003

Genome Res.

104

102

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Although much is known about genetic variation in human and African great ape (chimpanzee, bonobo, and gorilla) genomes, substantially less is known about variation in gene-expression profiles within and among these species. This information is necessary for defining transcriptional regulatory networks that contribute to complex phenotypes unique to humans or the African great apes. We took a systematic approach to this problem by investigating gene-expression profiles in well-defined cell populations from humans, bonobos, and gorillas. By comparing these profiles from 18 human and 21 African great ape primary fibroblast cell lines, we found that gene-expression patterns could predict the species, but not the age, of the fibroblast donor. Several differentially expressed genes among human and African great ape fibroblasts involved the extracellular matrix, metabolic pathways, signal transduction, stress responses, as well as inherited overgrowth and neurological disorders. These gene-expression patterns could represent molecular adaptations that influenced the development of species-specific traits in humans and the African great apes.

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“…Therefore, attempts have been made to develop rapid and specific methods to identify each nucleotidase, overcoming the presence of nonspecific phosphatases and the overlapping substrate specificity [28]. Human skin fibroblasts are thought to mirror impairments occurring in CNS of neurologically impaired patients and several researches point at the potential usefulness of these cells as experimental models and to help diagnose and treatment of neurological disorders [29]. Primary cultures of fibroblasts from patients have actually revealed a wealth of information on how neurological disorders occur and they seemed a very useful source for our study as well.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Nucleotidase Responsible for the AMP Hydrolysing Hyperactivity Associated with Neurological and Developmental Disorders

et al. 2007

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Nucleoside monophosphate phosphohydrolases comprise a family of enzymes dephosphorylating nucleotides both in intracellular and extracellular compartments. Members of this family exhibit different sequence, location, substrate specificity and regulation. Besides the ectosolic 5'-nucleotidase, several cytosolic and one mitochondrial enzymes have been described. Nevertheless, researchers refer any AMP-dephosphorylating activity to as 5'-nucleotidase, lacking a more accurate identification. Increase of AMP hydrolysing activity has been associated with neurological and developmental disorders. The identification of the specific enzyme involved in these pathologies would be fundamental for the comprehension of the linkage between the enzyme activity alteration and brain functions. We demonstrate that the described neurological symptoms are associated with increased ectosolic 5'-nucleotidase activity on the basis of radiochemical assays and immunoblotting analysis. Furthermore, present data evidence that the assay conditions normally applied for the determination of cytosolic 5'-nucleotidases activity in crude extracts are affected by the presence of solubilised ectosolic nucleotidase.

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Fibroblast models of neurological disorders: fluorescence measurement studies

Cited by 65 publications

References 29 publications

Up-regulation of Glycohydrolases in Alzheimer's Disease Fibroblasts Correlates with Ras Activation

Up-regulation of Glycohydrolases in Alzheimer's Disease Fibroblasts Correlates with Ras Activation

Comparative Analysis of Gene-Expression Patterns in Human and African Great Ape Cultured Fibroblasts

Identification of the Nucleotidase Responsible for the AMP Hydrolysing Hyperactivity Associated with Neurological and Developmental Disorders

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