Manuel Sanchez-Martin

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Verified

Manuel verified their affiliation via an institutional email.

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• PhD
• Lecturer at University of Salamanca

Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully...

In recent years, targeted genome editing has emerged as an indispensable tool for creating animal models, facilitating a comprehensive exploration of the molecular mechanisms governing a myriad of biological processes. Within this scientific landscape, the investigation of meiosis in mice has attracted considerable attention across numerous researc...

Meiosis, a reductional cell division, relies on precise initiation, maturation, and resolution of crossovers (COs) during prophase I to ensure the accurate segregation of homologous chromosomes during metaphase I. This process is regulated by the interplay of RING-E3 ligases such as RNF212 and HEI10 in mammals. In this study, we functionally charac...

Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration and is usually associated with mutations in the PRPH2 gene. We aimed to generate and characterize a mouse model with the p.Arg195Leu mutation previously described in patients. Heterozygous ( Prph2 WT/KI ) and h...

Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminisce...

Collagen VI Related Dystrophies (COL6-RD) are congenital muscle diseases, typically inherited as an autosomal dominant trait. A frequent type of mutation involves glycine substitutions in the triple helical domain of collagen VI alpha chains, exerting a dominant-negative effect on the unaltered protein. Despite this, no prior animal model captured...

Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, which includes the BCR-ABL1 fusion oncogene. C3G, a guanine nucleotide exchange factor, interacts with and is phosphorylated by BCR-ABL1 in CML cells. The RAPGEF1 gene, encoding C3G, is also involved in the Philadelphia chromosome translocation in CML. The study invest...

Rho GTPases are molecular switches regulating multiple cellular processes. To investigate the role of RhoA in normal intestinal physiology, we used a conditional mouse model overexpressing a dominant negative RhoA mutant (RhoAT19N) in the intestinal epithelium. Although RhoA inhibition did not cause an overt phenotype, increased levels of nuclear β...

Background Luminal A tumours generally have a favourable prognosis but possess the highest 10‐year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post‐diagnosis. Identifying such patients is crucial as long‐term relapsers could benefit from extended hormone therapy, while early relapsers m...

Brain-derived neurotrophic factor (BDNF) plays a critical role in postnatal development by modulating the architecture of specific neuronal populations and brain areas. However, the precise molecular program controlling this differential responsiveness to BDNF is still unclear. In the present study, we describe that this program is governed by the...

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N⁷-guanosine...

Background Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers, with a quarter recurring within five years. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers may require aggressive treat...

Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers. From those that relapse, a quarter of them do it within five years after diagnosis. Identifying such patients is crucial, as long-term relapsers could benefit from extended hormone therapy, whereas early relaps...

Purpose Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration, usually associated with mutations in the PRPH2 gene. We aimed to generate and characterize a mouse model with the p.Arg195Leu mutation previously described in patients. Methods Heterozygous (Prph2WT/KI...

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N ⁷ -methylguanosine (m ⁷ G) transferase METTL1 is highly expressed in prim...

The circadian clock controls behavior and physiology. Presently, there is clear evidence of a connection between this timing system and cancer development/progression. Moreover, circadian rhythm consideration in the therapeutic action of anticancer drugs can enhance the effectiveness of cancer therapy. Nanosized drug delivery systems (DDS) have bee...

The R-RAS2 GTP hydrolase (GTPase) (also known as TC21) has been traditionally considered quite similar to classical RAS proteins at the regulatory and signaling levels. Recently, a long-tail hotspot mutation targeting the R-RAS2/TC21 Gln⁷² residue (Q72L) was identified as a potent oncogenic driver. Additional point mutations were also found in othe...

Adult-type granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex cord–stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the transcription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid....

Meiosis is a highly conserved specialized cell division process that generates haploid gametes. Many of its events are associated with dynamically regulated chromosomal structures and chromatin remodeling, which are mainly modulated by histone modifications. Histone H1 is a linker histone essential for packing the nucleosome into higher-order struc...

Colorectal cancer causes >900,000 deaths every year and a deeper understanding of the molecular mechanisms underlying this disease will contribute to improve its clinical management and survival. Myosin Vb (MYO5B) regulates intracellular vesicle trafficking, and inactivation of this myosin disrupts the polarization and differentiation of intestinal...

Colorectal cancer causes >900,000 deaths every year and a deeper understanding of the molecular mechanisms underlying this disease will contribute to improve its clinical management and survival. Myosin Vb (MYO5B) regulates intracellular vesicle trafficking, and inactivation of this myosin disrupts the polarization and differentiation of intestinal...

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet form...

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somat...

Gastric cancer constitutes the third leading cause of cancer mortality worldwide and tumors with diffuse histology have poor prognosis and low response rates to therapy. Missense mutations in the RHOA (Ras homolog family member A) GTPase have recently been identified in 24% of patients with diffuse gastric cancer. RHOA mutations are not randomly di...

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerfu...

Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B –(c.92delT) in two sisters with POI. In vitro studies revealed that this v...

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerfu...

A missense change in RRAS2 (Gln⁷² to Leu), analogous to the Gln⁶¹-to-Leu mutation of RAS oncoproteins, has been identified as a long-tail hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains understudied. Here we show, using an inducible knockin mouse model, that R-Ras2Q72L trigge...

Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK) BCR/ABL1. TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during tr...

Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxida...

Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK) BCR/ABL1. TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during tr...

RUNX1-related disorder (RUNX1-RD) is caused by germline variants affecting the RUNX1 gene. This rare, heterogeneous disorder has no specific clinical or laboratory phenotype, making genetic diagnosis necessary. Although international recommendations have been established to classify the pathogenicity of variants, identifying the causative alteratio...

Simple Summary In the last two decades, the therapeutic landscape of several tumors have changed profoundly with the introduction of drugs against proteins encoded by oncogenes. Oncogenes play an essential role in human cancer and when their encoded proteins are inhibited by specific drugs, the tumoral process can be reverted or stopped. An example...

The constitutively active tyrosine kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent health...

Significance In this study, we report a unique and necessary function for the HoxC gene cluster in the development of some ectodermal organs, as illustrated both by the hair and nail phenotype displayed by mice lacking the Hoxc13 function and by the congenital anonychia (absence of nails) in full HoxC cluster mutants. We show that Hoxc genes are ac...

Meiotic reductional division depends on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC has eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine m...

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP , an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a...

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as...

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as...

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease produced by a unique oncogenic event involving the constitutively active tyrosine kinase (TK) BCR/ABL1 . TK activity explains most features of CML, such as tumor development and maintenance. TK-inhibitory (TKI) drugs have changed its prognosis and natural history. Unfortunately, th...

Huntington's disease and X-linked dystonia parkinsonism are two monogenic basal ganglia model diseases. Huntington's disease is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene leading to several toxic interactions of both the expanded CAG-containing mRNA and the polyglutamine-containing protein, while X-linked d...

Vertebrate Hox genes are key players in the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here we set up to analyze their elusive function in the ectoder...

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP , an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP kn...

Meiotic reductional division is dependent on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC is formed of eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility...

The Nomo1 gene mediates a wide range of biological processes of importance in embryonic development. Accordingly, constitutive perturbation of Nomo1 function may result in myriad developmental defects that trigger embryonic lethality. To extend our understanding of Nomo1 function in postnatal stages and in a tissue-specific manner, we generated a c...

Hydrogen peroxide (H2O2) is generated in cells and plays an important role as a signalling molecule. It has been reported that H2O2 is involved in physiological and pathological processes in skeletal muscle. However, H2O2 detection in cells with traditional techniques produces frequent artefacts. Currently, the HyPer biosensor detects intracellular...

Unlike other species, prion disease has never been described in dogs even though they were similarly exposed to the bovine spongiform encephalopathy (BSE) agent. This resistance prompted a thorough analysis of the canine PRNP gene and the presence of a negatively charged amino acid residue in position 163 was readily identified as potentially funda...

The regulation of protein function by reversible oxidation is increasingly recognized as a key mechanism for the control of cellular signaling, modulating crucial biological processes such as cell differentiation. In this scenario, NADPH oxidases must occupy a prominent position. Our results show that hematopoietic stem and progenitor cells express...

The Nomo1 gene mediates a wide range of biological processes of importance in embryonic development. Accordingly, constitutive perturbation of Nomo1 function may result in myriad developmental defects that trigger embryonic lethality. To extend our understanding of Nomo1 function in postnatal stages and in a tissue-specific manner, we generated a c...

Unlike other species, such as cattle, cats or humans, prion disease has never been described in dogs, even though they were similarly exposed to the bovine spongiform encephalopathy (BSE) agent. This resistance prompted a thorough analysis of the canine PRNP gene and the presence of a negatively charged amino acid residue in position 163 was readil...

Specific variations in the amino acid sequence of prion protein (PrP) are key determinants of susceptibility to prion diseases. We previously showed that an amino acid substitution specific to canids confers resistance to prion diseases when expressed in mice and demonstrated its dominant-negative protective effect against a variety of infectious p...

Ubiquitin-specific protease 26 (USP26) is a deubiquitylating enzyme belonging to the USPs family with a transcription pattern restricted to the male germline. Since protein ubiquitination is an essential regulatory mechanism during meiosis, many efforts have been focused on elucidating the function of USP26 and its relationship with fertility. Duri...

The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a ‘zipper’-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA doub...

La modificación genética del ratón y de otros organismos modelo se ha revolucionado con la irrupción de la tecnología CRISPR, la cual ha permitido editar el genoma de cualquier organismo de una forma tan precisa, sencilla y universal que no tiene comparación con ninguna otra herramienta usada hasta ahora. Sin embargo, esta tecnología no esta libre...

CRISPR/Cas9 enables the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null r...

Genome-editing nucleases like the popular CRISPR/Cas9 enable the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks (DSBs) within a genome. In most cases, when a DNA template is not present, the DSB is repaired by nonhomologous end joining (NHEJ), resulting in small nucleotide insertions or deletions...

Lung cancer represents the leading cause of cancer death worldwide [1]. Because of that, intense efforts are being devoted to the development of novel therapeutic strategies to fight the disease [2]. In this respect, identification of new oncogenic drivers offers therapeutic opportunities in tumours in which those molecules or other cooperating ele...

Meiotic recombination generates crossovers which are essential to ensure genome haploidization. The ubiquitin proteasome system regulates meiotic recombination through its association to the synaptonemal complex, a 'zipper'-like structure that holds homologs and provides the structural framework for meiotic recombination. Here we show that the test...

While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion...

Numerous pathophysiological processes are driven by cellular signalling pathways where hydrogen peroxide (H2O2) seems to play an important role as a molecular signal. We have used a genetically encoded hydrogen peroxide biosensor, HyPer, in order to monitor and quantify intracellular H2O2 changes. We combined different approaches, based in direct m...

Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc conformations a...

One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneou...

PrP sequence alignments. A. PrP protein amino acid (91–230) alignment (dog PrP numbering) of GenBank published sequences containing Asp or Glu at codon 163. The residues present at positions 101 and 163 are highlighted. Two different sequences for coyote differing at codon 101, and 4 different sequences for dog differing at codons 101 and 163 are s...

Local environments of mouse N158 from PrP PDB ID 1XYX (gray); PDB ID 2L39 (dark pink) & PDB ID 4MA8 (light pink) and D158 (equivalent to position 163 from canine PrP) PDB ID 1XYK (green) structures and conformers for Arg135 (R135) in the same datasets. Residue numbers for R135 are labeled with the PDB code as sticks. Comparison of local environment...

Level of PrPC expression in brains from different species. To compare the PrPC expression levels present in the brains from different species a serial dilution (1:4, 1:8, 1:16 and 1:32 and 1:64) was performed. Dog 1: Cocker Spaniel. Dog 2: German Wirehaired Pointer. Rabbit: New Zealand white rabbit. Cat: European shorthaired. Mouse: C57BL6 mouse. U...

Remnant signal of BSE-C inoculum not submitted to PMCA and demonstration that cattle PrPC present in the inocula does not sustain BSE-C propagation. Western blot showing the same 1:3 dilution of the BSE-C (isolate 1) seed used in dog brain homogenates submitted to PMCA (procedure D1). The lack of remnant signal of the seed applied at 30% on the sub...

PrP protein amino acid alignment (residues 91–230, dog PrP numbering) from several dog breeds. *: Heterozygous Ser-Gly at position 101. Identical amino acids are indicated by dots. Accession numbers: doPrP (FJ870767.1); Cocker Spaniel (KY649551); German Wirehaired Pointer (KY649553); Australian Shepherd (KY649552); Pyrenean Shepherd (KY649554); Bel...

PrP expression levels of Tg402 and Tg403 compared to C57BL/6 and Tga20 mice. 10% brain homogenates from C57BL/6, Tg402 and Tg403 mice were diluted 1:20, 1:40, 1:80, 1:160 and 1:320 and diluted 10% brain homogenate from Tga20 diluted 1:40, 1:80, 1:160, 1:320 and 1:640 were analyzed by Western blot using monoclonal antibody Saf-83 (1:400). The PrP ex...

PrP expression levels of transiently transfected cells compared to PrP expression levels in C57BL/6 mouse brain homogenate. 10% C57BL/6 mouse brain homogenate was diluted (1:1, 1:2, 1:4, 1:8, 1:16 and 1:32) equal to the homogenates from cells transfected with the following plasmids: pCMV N158 (wt) mouse PrP, pCMV E158 mouse PrP and pCMV D158 mouse...

Immunohistochemical analysis of PrPC expression in homozygous Tg402 and Tg403 compared to C57BL/6. Cerebral cortex sections from Tg402, Tg403 and C57BL/6 mice were used to compare the localization of PrPC expression. A fine granular neuropil immunolabeling (corresponding to PrPC on the dendrite cell membrane) and absence of labeling within the peri...

Hydrogen peroxide (H2O2) is one of the reactive oxygen species (ROS) that seems to play an essential role in cellular signalling pathways coupled to frequent pathophysiological processes. However, using traditional methodology it is virtually impossible to identify and quantify H2O2 flux in cells. We have developed methodological approaches based o...

CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained an...

Meiotic recombination generates crossovers between homologous chromosomes that are essential for genome haploidization. The synaptonemal complex is a 'zipper'-like protein assembly that synapses homologue pairs together and provides the structural framework for processing recombination sites into crossovers. Humans show individual differences in th...

1. Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC). Universidad de Salamanca/CSIC. Salamanca, España. 2. Instituto Biosanitario de Salamanca (IBSAL). Salamanca, España. 3. Departamento de Bioquímica y Biología Molecular I. Facultad de Biología. Universidad Complutense de Madrid. Madrid, España. 4. Departamento de Medicina. Universi...

One of the characteristics of prions is their ability to infect some species but not others. Thus, prion resistant species have been of special interest in the field because of their potential in deciphering essential determinants for susceptibility. Previously, our group has been involved in the development of different in vitro and in vivo models...

Recent studies in mice and humans have shown that targeted genome-editing technologies can correct disease-causing genetic mutations, offering a powerful approach to treat many somatic human diseases. Human infertility is a prevalent disease with a solid genetic basis and for which the identification of the germline disease-causing mutation is now...

Interspecies transmission of prions is a well-established phenomenon, both experimentally and under field conditions. Upon passage through new hosts, prion strains have proven their capacity to change their properties and this is a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption...