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Dive into the research topics where Maria de Haro is active.

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Featured researches published by Maria de Haro.


Journal of Biological Chemistry | 2006

CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation.

Ismael Al-Ramahi; Yung C. Lam; Hung Kai Chen; Beatrice De Gouyon; Minghang Zhang; Alma M. Perez; Joana Branco; Maria de Haro; Cam Patterson; Huda Y. Zoghbi; Juan Botas

CHIP (C terminus of Hsc-70 interacting protein) is an E3 ligase that links the protein folding machinery with the ubiquitin-proteasome system and has been implicated in disorders characterized by protein misfolding and aggregation. Here we investigate the role of CHIP in protecting from ataxin-1-induced neurodegeneration. Ataxin-1 is a polyglutamine protein whose expansion causes spinocerebellar ataxia type-1 (SCA1) and triggers the formation of nuclear inclusions (NIs). We find that CHIP and ataxin-1 proteins directly interact and co-localize in NIs both in cell culture and SCA1 postmortem neurons. CHIP promotes ubiquitination of expanded ataxin-1 both in vitro and in cell culture. The Hsp70 chaperone increases CHIP-mediated ubiquitination of ataxin-1 in vitro, and the tetratricopeptide repeat domain, which mediates CHIP interactions with chaperones, is required for ataxin-1 ubitiquination in cell culture. Interestingly, CHIP also interacts with and ubiquitinates unexpanded ataxin-1. Overexpression of CHIP in a Drosophila model of SCA1 decreases the protein steady-state levels of both expanded and unexpanded ataxin-1 and suppresses their toxicity. Finally we investigate the ability of CHIP to protect against toxicity caused by expanded polyglutamine tracts in different protein contexts. We find that CHIP is not effective in suppressing the toxicity caused by a bare 127Q tract with only a short hemaglutinin tag, but it is very efficient in suppressing toxicity caused by a 128Q tract in the context of an N-terminal huntingtin backbone. These data underscore the importance of the protein framework for modulating the effects of polyglutamine-induced neurodegeneration.


Neuron | 2010

Matrix Metalloproteinases are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington’s Disease

John P. Miller; Jennifer Holcomb; Ismael Al-Ramahi; Maria de Haro; Juliette Gafni; Ningzhe Zhang; Eugene Kim; Mario Sanhueza; Cameron Torcassi; Seung Kwak; Juan Botas; Robert E. Hughes

Proteolytic cleavage of huntingtin (Htt) is known to be a key event in the pathogenesis of Huntingtons disease (HD). Our understanding of proteolytic processing of Htt has thus far focused on the protease families-caspases and calpains. Identifying critical proteases involved in Htt proteolysis and toxicity using an unbiased approach has not been reported. To accomplish this, we designed a high-throughput western blot-based screen to examine the generation of the smallest N-terminal polyglutamine-containing Htt fragment. We screened 514 siRNAs targeting the repertoire of human protease genes. This screen identified 11 proteases that, when inhibited, reduced Htt fragment accumulation. Three of these belonged to the matrix metalloproteinase (MMP) family. One family member, MMP-10, directly cleaves Htt and prevents cell death when knocked down in striatal Hdh(111Q/111Q) cells. Correspondingly, MMPs are activated in HD mouse models, and loss of function of Drosophila homologs of MMPs suppresses Htt-induced neuronal dysfunction in vivo.


PLOS Genetics | 2005

dAtaxin-2 Mediates Expanded Ataxin-1-Induced Neurodegeneration in a Drosophila Model of SCA1

Ismael Al-Ramahi; Alma M. Perez; Janghoo Lim; Minghang Zhang; Rie D Sørensen; Maria de Haro; Joana Branco; Stefan M. Pulst; Huda Y. Zoghbi; Juan Botas

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders sharing atrophy of the cerebellum as a common feature. SCA1 and SCA2 are two ataxias caused by expansion of polyglutamine tracts in Ataxin-1 (ATXN1) and Ataxin-2 (ATXN2), respectively, two proteins that are otherwise unrelated. Here, we use a Drosophila model of SCA1 to unveil molecular mechanisms linking Ataxin-1 with Ataxin-2 during SCA1 pathogenesis. We show that wild-type Drosophila Ataxin-2 (dAtx2) is a major genetic modifier of human expanded Ataxin-1 (Ataxin-1[82Q]) toxicity. Increased dAtx2 levels enhance, and more importantly, decreased dAtx2 levels suppress Ataxin-1[82Q]-induced neurodegeneration, thereby ruling out a pathogenic mechanism by depletion of dAtx2. Although Ataxin-2 is normally cytoplasmic and Ataxin-1 nuclear, we show that both dAtx2 and hAtaxin-2 physically interact with Ataxin-1. Furthermore, we show that expanded Ataxin-1 induces intranuclear accumulation of dAtx2/hAtaxin-2 in both Drosophila and SCA1 postmortem neurons. These observations suggest that nuclear accumulation of Ataxin-2 contributes to expanded Ataxin-1-induced toxicity. We tested this hypothesis engineering dAtx2 transgenes with nuclear localization signal (NLS) and nuclear export signal (NES). We find that NLS-dAtx2, but not NES-dAtx2, mimics the neurodegenerative phenotypes caused by Ataxin-1[82Q], including repression of the proneural factor Senseless. Altogether, these findings reveal a previously unknown functional link between neurodegenerative disorders with common clinical features but different etiology.


Cell and Tissue Research | 2010

Detailed analysis of leucokinin-expressing neurons and their candidate functions in the Drosophila nervous system

Maria de Haro; Ismael Al-Ramahi; Jonathan Benito-Sipos; Begoña López-Arias; Belén Dorado; Jan A. Veenstra; Pilar Herrero

The distribution of leucokinin (LK) neurons in the central nervous system (CNS) of Drosophila melanogaster was described by immunolabelling many years ago. However, no detailed underlying information of the input or output connections of their neurites was then available. Here, we provide a more accurate morphological description by employing a novel LK-specific GAL4 line that recapitulates LK expression. In order to analyse the possible afferent and efferent neural candidates of LK neurons, we used this lk-GAL4 line together with other CNS-Gal4 lines, combined with antisera against various neuropeptides or neurotransmitters. We found four kinds of LK neurons in the brain. (1) The lateral horn neurons connect the antennal glomerula to the mushroom bodies. (2) The suboesophageal neurons connect the gustatory receptors to the suboesophageal ganglia and ventral nerve cord. (3) The anterior neurons innervate the corpus cardiacum of the ring gland but LK expression is surprisingly not detectable from the third instar onwards in these neurons. (4) A set of abdominal ganglion neurons connect to the dorsal median tract in larvae and send their axons to a segmental muscle 8. Thus, the methods employed in our study can be used to identify individual neuropeptidergic neurons and thereby characterize functional cues or developmental transformations in their differentiation.


PLOS Genetics | 2012

A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease.

John P. Miller; Bridget E. Yates; Ismael Al-Ramahi; Ari E. Berman; Mario Sanhueza; Eugene Kim; Maria de Haro; Francesco DeGiacomo; Cameron Torcassi; Jennifer Holcomb; Juliette Gafni; Sean D. Mooney; Juan Botas; Robert E. Hughes

A genome-scale RNAi screen was performed in a mammalian cell-based assay to identify modifiers of mutant huntingtin toxicity. Ontology analysis of suppressor data identified processes previously implicated in Huntingtons disease, including proteolysis, glutamate excitotoxicity, and mitochondrial dysfunction. In addition to established mechanisms, the screen identified multiple components of the RRAS signaling pathway as loss-of-function suppressors of mutant huntingtin toxicity in human and mouse cell models. Loss-of-function in orthologous RRAS pathway members also suppressed motor dysfunction in a Drosophila model of Huntingtons disease. Abnormal activation of RRAS and a down-stream effector, RAF1, was observed in cellular models and a mouse model of Huntingtons disease. We also observe co-localization of RRAS and mutant huntingtin in cells and in mouse striatum, suggesting that activation of R-Ras may occur through protein interaction. These data indicate that mutant huntingtin exerts a pathogenic effect on this pathway that can be corrected at multiple intervention points including RRAS, FNTA/B, PIN1, and PLK1. Consistent with these results, chemical inhibition of farnesyltransferase can also suppress mutant huntingtin toxicity. These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntingtons disease.


eLife | 2016

TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau

Maxime W.C. Rousseaux; Maria de Haro; Cristian A. Lasagna-Reeves; Antonia De Maio; Jeehye Park; Paymaan Jafar-Nejad; Ismael Al-Ramahi; Ajay Sharma; Lauren See; Nan Lu; Luis Vilanova-Velez; Tiemo J. Klisch; Thomas F. Westbrook; Juan C. Troncoso; Juan Botas; Huda Y. Zoghbi

Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinsons disease (PD); neuronal accumulation of tau is a hallmark of Alzheimers disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points. DOI: http://dx.doi.org/10.7554/eLife.19809.001


Neuron | 2016

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model.

Cristian A. Lasagna-Reeves; Maria de Haro; Shuang Hao; Jeehye Park; Maxime W.C. Rousseaux; Ismael Al-Ramahi; Paymaan Jafar-Nejad; Luis Vilanova-Velez; Lauren See; Antonia De Maio; Larissa Nitschke; Zhenyu Wu; Juan C. Troncoso; Thomas F. Westbrook; Jianrong Tang; Juan Botas; Huda Y. Zoghbi

Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.


PLOS Genetics | 2013

Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy

Maria de Haro; Ismael Al-Ramahi; Karlie Jones; Jerrah K. Holth; Lubov Timchenko; Juan Botas

We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA–binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1.


Cell systems | 2018

High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration

Ismael Al-Ramahi; Boxun Lu; Simone Di Paola; Kaifang Pang; Maria de Haro; Ivana Peluso; Tatiana Gallego-Flores; Nazish T. Malik; Kelly Erikson; Benjamin A. Bleiberg; Matthew Avalos; George Fan; Laura Elizabeth Rivers; Andrew M. Laitman; Javier R. Diaz-García; Marc Hild; James Palacino; Zhandong Liu; Diego L. Medina; Juan Botas

Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.


eLife | 2017

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Ismael Al-Ramahi; Sai Srinivas Panapakkam Giridharan; Yu-Chi Chen; Samarjit Patnaik; Nathaniel Safren; Junya Hasegawa; Maria de Haro; Amanda K Wagner Gee; Steven A. Titus; Hyunkyung Jeong; Jonathan H. Clarke; Dimitri Krainc; Wei Zheng; Robin F. Irvine; Sami J. Barmada; Marc Ferrer; Noel Southall; Lois S. Weisman; Juan Botas; Juan J. Marugan

The discovery of the causative gene for Huntington’s disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington’s disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington’s disease, and potentially for other neurodegenerative disorders.

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Ismael Al-Ramahi

Baylor College of Medicine

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Juan Botas

Baylor College of Medicine

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Huda Y. Zoghbi

Baylor College of Medicine

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Joana Branco

Baylor College of Medicine

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Minghang Zhang

Baylor College of Medicine

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Alma M. Perez

Baylor College of Medicine

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Antonia De Maio

Boston Children's Hospital

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Cameron Torcassi

Buck Institute for Research on Aging

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Cristian A. Lasagna-Reeves

University of Texas Medical Branch

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