Validating indicators of CNS disorders in a swine model of neurological disease (original) (raw)
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A porcine model of neurofibromatosis type 1 that mimics the human disease
JCI insight, 2018
Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyper...
Neuroscience, 2007
Completion of the Human Genome Project and recent developments in proteomics make it possible to systematically generate affinity reagents to a large portion of the proteome. Recently an antibody-based human protein atlas covering many organs including four areas of the brain has been released (www.proteinatlas.org). Due to the heterogeneity, size, and availability of tissue a more thorough analysis of the human brain is associated with considerable difficulties. Here we applied 120 antibodies raised against 112 human gene products to the smaller rat brain, a rodent animal model, where a single section represents a 'superarray' including many brain areas, and consequently allowing analysis of a huge number of cell types and their neurochemicals. Immunoreactive structures were seen in the investigated brain tissue after incubation with 56 antibodies (46.6%), of which 25 (20.8%) showed a clearly discrete staining pattern that was limited to certain areas, or subsets of brain cells. Bioinformatics, pre-adsorption tests and Western blot analysis were applied to identify non-specific antibodies. Eleven antibodies, including such raised against four 'ambiguous' proteins, passed all validation criteria, and the expression pattern and subcellular distribution of these proteins were studied in detail. To further explore the potential of the systematically generated antibodies, all 11 antibodies that passed validation were used to analyze the spinal cord and lumbar dorsal root ganglia after unilateral transection of the sciatic nerve. Discrete staining patterns were observed for four of the proteins, and injury-induced regulation was found for one of them. In conclusion, the study presented here suggests that a significant portion (10%) of the antibodies generated to a human protein can be used to analyze orthologues present in the rodent brain and to produce a proteinbased atlas of the rodent brain. It is hoped that this type of antibody-based, high throughput screening of brain tissue from various rodent disease models will provide new information on the brain chemical neuroanatomy and insights in processes underlying neurological pathologies. (J. Mulder). Abbreviations: ABP, albumin-binding protein; CCDC22, coiled-coil domain containing protein 22; CXorf33, chromosome X open reading frame 33; DRG, dorsal root ganglion; Gb, gigabase; GOLGA5, golgin subfamily A member 5; HiFo, hippocampal formation; HPA, human protein atlas; HSPA2, heat shock-related 70 kDa protein 2; NHP2L1, high mobility group-like nuclear protein 2 homologue 1; PABPC, poly(A) binding protein; PABPC5, poly(A) binding protein cytoplasmic 5; PB, phosphate buffer; PBS, phosphate-buffered saline; PDXP, pyridoxal phosphate phosphatase; PrEST, protein epitope signature tag; RNBP, renin-binding protein; SYAP1, synapse-associated protein 1; ZFY, zinc finger Y-chromosomal protein.
Mouse Models of Neurofibromatosis 1 and 2
Neoplasia, 2002
The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.
Animal models for neural diseases
Toxicologic pathology, 2011
''Animal Models of Neural Disease'' was the focus of General Session 5 at a 2010 scientific symposium that was sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The objective was to consider issues that dictate the choice of animal models for neuropathology-based studies used to investigate neurological diseases and novel therapeutic agents to treat them. In some cases, no animal model exists that recapitulates the attributes of the human disease (e.g., fibromyalgia syndrome). Alternatively, numerous animal models are available for other conditions, so an essential consideration is selecting the most appropriate experimental system (e.g., Alzheimer's disease). New technologies (e.g., genetically engineered rodent models) promise the opportunity to generate suitable animal models for syndromes that currently lack any in vivo animal model, while in vitro models offer the opportunity to evaluate xenobiotic effects in specific neural cell populations. The complex nature of neurological disease requires regular reassessment of available and potential options to ensure that animal-derived data sets support translational medicine efforts to improve public health.
Current status and recommendations for biomarkers and biobanking in neurofibromatosis
Neurology, 2016
Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in dec...
Identification of the neurofibromatosis type 1 gene product
Proceedings of the National Academy of Sciences, 1991
The gene for neurofibromatosis type 1 (NF1) was recently identified by positional cloning. The complete cDNA encodes a polypeptide of 2818 amino acids. To study the NF1 gene product, antibodies were raised against both fusion proteins and synthetic peptides. Initial characterization of two anti-peptide antibodies and one fusion-protein antibody demonstrated a specific protein of approximately 250 kDa by both immunoprecipitation and immunoblotting. This protein was found in all tissues and cell lines examined and is detected in human, rat, and mouse tissues. To demonstrate that these antibodies specifically recognize the NF1 protein, additional fusion proteins containing the sequence specific to the synthetic peptide were generated. Both peptide antisera recognize the proper specific fusion proteins so generated. Immunoprecipitates using the peptide antisera were shown to recognize the same protein detected by immunoblotting with either the other peptide antiserum or the fusion-prote...