Rafael Vázquez-Manrique

Rafael Vázquez-Manrique
Instituto de Investigación Sanitaria La Fe | IISLAFE · Molecular, Cellular and Genomics Biomedicine Lab

PhD

About

66
Publications
8,504
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Introduction
Rafael Vázquez-Manrique currently works at the Molecular, Cellular and Genomics Biomedicine Lab, Instituto de Investigación Sanitaria La Fe. Rafael does research in Cell Biology, Developmental Biology and Genetics. Their most recent publication is 'USH2A Gene Editing Using the CRISPR System.'
Additional affiliations
May 2010 - May 2012
French Institute of Health and Medical Research
Position
  • Fellow
September 2008 - April 2010
French Institute of Health and Medical Research
Position
  • PostDoc Position
March 2003 - March 2008
University of Cambridge
Position
  • PostDoc Position

Publications

Publications (66)
Article
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are dis...
Article
Full-text available
Neurodegenerative disorders, caused by prone-to-aggregation proteins, such as Alzheimer disease or Huntington disease, share other traits such as disrupted homeostasis of essential metal ions, like copper. In this context, in an attempt to identify Cu2+ chelating agents, we study several organic compounds (ethylenediaminetetraacetic acid, phenylene...
Article
Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamin...
Article
Full-text available
Data from manual healthspan assays of the nematode Caenorhabditis elegans (C. elegans) can be complex to quantify. The first attempts to quantify motor performance were done manually, using the so-called thrashing or body bends assay. Some laboratories have automated these approaches using methods that help substantially to quantify these character...
Preprint
Full-text available
Protein homeostasis is crucial for viability of all organisms, and mutations that enhance protein aggregation cause different human pathologies, including polyglutamine (polyQ) diseases, such as some spinocerebellar ataxias or Huntington disease. Here, we report that neuronal Stomatin-like protein UNC-1 protects against aggregation of prone-to-aggr...
Preprint
Acute Myeloid Leukaemia is a complex heterogenous disease caused by clonal expansion of undifferentiated myeloid precursors. Recently, several haematological models have been developed with CRISPR/Cas9, using viral vectors, because blood cells are hard to transfect. To avoid virus disadvantages, we have developed a strategy to generate CRISPR const...
Article
Full-text available
Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together w...
Article
Full-text available
Huntington disease is a neurodegenerative condition for which there is no cure to date. Activation of AMP-activated protein kinase has previously been shown to be beneficial in in vitro and in vivo models of Huntington's disease. Moreover, a recent cross-sectional study demonstrated that treatment with metformin, a well-known activator of this enzy...
Article
Full-text available
Advances in genome engineering in the last decade, particularly in the development of programmable nucleases, have made it possible to edit the genomes of most cell types precisely and efficiently. Chief among these advances, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is a novel, versatile and easy-to-use too...
Article
Full-text available
In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans...
Conference Paper
Toxicity induced by proteins containing polyglutamines (polyQs) is the cause of different neurodegenerative diseases, such as Huntington’s disease (HD). Mutant huntingtin (mHtt) is prone to aggregation, due to an abnormally long polyQ at the N-terminal region, which is believed to cause aggregation of other molecules, and contributes to the toxicit...
Conference Paper
Activation of AMPK, a master regulator of the homeostasis of energy levels in the cell, has been shown to reduce toxicity induce both by mutant huntingtin and polyglutamines (polyQ) in both in vitro and in vivo models. Moreover, a cross-sectional study of the Enroll-HD database shows that metformin intake associates with better cognitive state of p...
Preprint
Full-text available
In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans...
Article
Full-text available
Usher syndrome (USH) is a rare autosomal recessive disease and the most common inherited form of combined visual and hearing impairment. Up to 13 genes are associated with this disorder, with USH2A being the most prevalent, due partially to the recurrence rate of the c.2299delG mutation. Excluding hearing aids or cochlear implants for hearing impai...
Article
Full-text available
Huntington’s disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a...
Poster
Mutant huntingtin (mHtt) is a molecule prone to aggregation due to the presence of an abnormally long tandem of glutamines (polyQs). The aggregation dynamics of mHtt, and other prone-to-aggregation proteins, is modulated by a range of molecules and pathways. For example, autophagy and the proteasome clear out the cell from these toxic molecules. Al...
Article
Full-text available
The AMP activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease...
Article
Full-text available
RNA interference (RNAi) is a widespread and widely exploited phenomenon. Here, we show that changing inositol 1,4,5-trisphosphate (IP3) signalling alters RNAi sensitivity in Caenorhabditis elegans. Reducing IP3 signalling enhances sensitivity to RNAi in a broad range of genes and tissues. Conversely up-regulating IP3 signalling decreases sensitivit...
Article
Full-text available
Background Usher syndrome is an autosomal recessive disease that associates sensorineural hearing loss, retinitis pigmentosa and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous. To date, 10 genes have been associated with the disease, making its molecular diagnosis based on Sanger sequencing, expensive and tim...
Article
Full-text available
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that R...
Article
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Author Summary Neuronal cell decline in neurodegenerative disease can be caused by inherited mutations and involves neuronal dysfunction followed by neuronal death. The ability of neurons to cope with the chronic stress induced by mutant protein expression may determine the course of their decline and eventual demise. Although the pathophysiologica...
Chapter
Ataxia describes neurological conditions consisting ofthe loss of the ability to coordinate muscular movements. These diseases show an extraordinary heterogeneity in clinical features but also in the molecular basis underlying the disease. Hence, it is critical to set up disease-specific models to investigate these conditions. In this regard, C. el...
Chapter
Several genes and pathways may act in a concerted and finely tuned fashion to regulate cell survival and longevity. Pathways that converge onto FOXO transcription factors have been the subject of particular attention because FOXO is a longevity-promoting factor that may be important throughout the entire lifetime of a living organism, as suggested...
Article
Based on the biosynthetic line of canthin-6-one alkaloids from their simple precursors such as tryptamine, the present work is focused on the study of alternative protocol of the Bischler-Napieralski reaction and has led to a full coverage of the different biosynthetic intermediates. Nanoparticles were also prepared as mimics of biosynthetic assemb...
Article
Full-text available
Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity i...
Article
Full-text available
One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expand...
Conference Paper
Full-text available
Background Huntington's disease (HD) is a neurodegenerative disorder induced by cell toxicity caused by polyglutamine (polyQ) expansion in the N-terminal region of huntingtin (Htt). We use C elegans expressing 128Q in neurons to screen for genes that modulate the early phases (neuron dysfunction) of mutant polyQ cytotoxicity. Using these worms we h...
Article
Full-text available
A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in...
Data
Table S1. List of the 2211 genes that caused lethality and developmental abnormalities when knocked-down by RNAi.
Data
Figure S1. Distribution of S scores for the primary screen in 128Q;rrf-3 nematodes. The graph shows the S scores for 4017 RNAi clones that did not elicit lethality or developmental abnormalities. The S score was calculated as [(Percent response - mean baseline)/mean baseline]. The maximally-achievable score is 4.55 (100% response to touch) and the...
Data
Table S3. List of the 662 genes that modified 128Q-neuron dysfunction when knocked-down by RNAi in the secondary screen.
Data
Table S4. List of the 15 genes that modified 19Q-neuron dysfunction when knocked-down by RNAi.
Data
Table S5. List of the 15 genes that modified 128Q-neuron dysfunction in the secondary screen and were previously reported to modify polyQ aggregation when knocked-down by RNAi.
Data
Table S6. Gene Ontology classification of genes that suppressed 128Q-neuron dysfunction when knocked-down by RNAi.
Data
Table S8. Modules (n = 137) generated by network-boosted analysis for suppression of 128Q-neuron dysfunction by RNAi.
Data
Table S2. List of the 3823 genes that either showed no effect or modified 128Q-neuron dysfunction when knocked-down by RNAi in the primary screen.
Data
Table S9. Modules (n = 105) generated by network-boosted analysis for aggravation of 128Q-neuron dysfunction by RNAi.
Data
Table S7. Gene Ontology classification of genes that aggravated 128Q-neuron dysfunction when knocked-down by RNAi.
Article
The nematode, Caenorhabditis elegans is an established model system that is particularly well suited to genetic analysis. C. elegans is easily manipulated and we have an in depth knowledge of many aspects of its biology. Thus, it is an attractive system in which to pursue integrated studies of signalling pathways. C. elegans has a complement of cal...
Article
Full-text available
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of...
Article
Full-text available
Caenorhabditis elegans has a complete annotated genome sequence that is augmented by increasing quantities of data from high-throughput postgenomic analyses. This has led to an increasing need to identify the biological functions of specific genes using reverse genetics, i.e., moving from gene to phenotype. Fundamental to this aim is the ability to...
Article
Full-text available
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare inherited disorder characterized by mild anemia and ataxia. XLSA/A is caused by mutations in the ABCB7 gene, which encodes a member of the ATP-binding cassette transporter family. Studies in yeast, mammalian cells, and mice have shown that ABCB7 functions in the transport of iron-sulfur (...
Article
Full-text available
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare inherited disorder characterized by mild anemia and ataxia. XLSA/A is caused by mutations in the ABCB7 gene, which encodes a member of the ATP-binding cassette transporter family. Studies in yeast, mammalian cells, and mice have shown that ABCB7 functions in the transport of iron-sulfur (...
Article
Background The FOXO longevity pathway and β-catenin pathway are major signalling systems that may regulate cell survival. Whether GSK3/β-catenin may interact with longevity signalling to regulate diseased neuron survival and whether this may translate into the modification of human neurodegenerative disease remain unknown. Aims We aimed to test the...
Article
Background Huntington's disease (HD) is a neurodegenerative pathology induced by cell toxicity caused by polyglutamine (polyQ) expansion in the N terminal end of huntingtin (htt). Using C elegans transgenics that express expanded polyQs in neurons, we identified a gene network that is centred onto FoxO and that protects neurons from expanded polyQs...
Article
Full-text available
When Caenorhabditis elegans encounters an unfavourable stimulus at its anterior, it responds by initiating an avoidance response, namely reversal of locomotion. The amphid neurons, ASHL and ASHR, are polymodal in function, with roles in the avoidance responses to high osmolarity, nose touch, and both volatile and non-volatile repellents. The mechan...
Article
Gene targeting is widely used for the precise manipulation of genes. However, in the model organism Caenorhabditis elegans non-transposon mediated gene targeting remains laborious, and as a result has not been widely used. One obstacle to the wider use of this approach is the difficulty of identifying homologous recombination events amongst non-spe...
Data
Full-text available
Supplementary figures and legends, pdf, contains: Supplementary figure 1: gon-2(RNAi) on gtl-1(ok375) worms increases variability in the defecation cycle. Supplementary figure 2: gtl-1 is expressed in the intestine whilst gtl-2 is expressed in the pharynx and excretory cell.
Article
Full-text available
Migration of cells within epithelial sheets is an important feature of embryogenesis and other biological processes. Previous work has demonstrated a role for inositol 1,4,5-trisphosphate (IP(3))-mediated calcium signalling in the rearrangement of epidermal cells (also known as hypodermal cells) during embryonic morphogenesis in Caenorhabditis eleg...
Data
The epidermal cells of plc-1(tm753) embryos are defective in migration. Time lapse confocal microscopy was used to follow the migration of epidermal cells during ventral enclosure in plc-1(tm753) embryos expressing AJM-1::GFP. In this embryo the leading cells fail to reach the midline and their opposing cell. As a result of this, the anterior part...
Data
Strains used in this work. (0.07 MB DOC)
Data
Molecular lesions in the plc-1(tm738) and plc-1(tm753) alleles. (A) The genomic organisation of the plc-1 gene showing exons (blue boxes) and introns (black lines). The extent of the deletions in tm753 and tm738 are shown in red. tm738 is a small deletion but produces a change of frame which is likely to result in a severely truncated protein and i...
Article
Full-text available
Ultradian rhythms, rhythms with a period of less than 24 hours, are a widespread and fundamental aspect of life. The mechanisms underlying the control of such rhythms remain only partially understood. Defecation in C. elegans is a very tightly controlled rhythmic process. Underlying the defecation motor programme is an oscillator which functions in...
Article
The genome of the nematode Caenorhabditis elegans is unusual among eukaryotes, in that it contains operons. Approximately 15% of genes in the worm are clustered into groups of between two and eight genes, which are under the control of shared regulatory sequences. Polycistronic transcripts from such operons are trans-spliced, during transcription,...
Article
Coenzyme Q (Q) and the genes involved in its biosynthesis are involved in aging and development of Caenorhabditis elegans. Q is synthesized by at least eight highly conserved nuclear coq genes, but this biosynthesis pathway and its regulation is not known. The coq-8 gene sequence has homology to the ABC-1 family kinases and is the only known candid...
Article
Full-text available
Friedreich ataxia is an autosomal recessive neurological disorder caused by deficiency of the mitochondrial protein frataxin. Studies in patient cells, mouse knockout animals, and Saccharomyces cerevisiae models have suggested several hypotheses on the frataxin function, but the full physiology of frataxin in mitochondria has not been well establis...