Bio

Bio


• In October 2017 my previous research related to Alzheimer's signs in dolphins got worldwide recognition appearing in tv and newspapers from all around the world such Newsweek, The Times, CBS, Discover, The Chicago Post, Los Angeles Times, Nature, National Geographic Italy (2018) and more. I recently joined to Stanford University (Stem Cell Transplantation and Regenerative Medicine).

• My initial training focused on marine biology, with special emphasis on trace metal pollution. This work, which involved collaborations with different governmental, private (as Venezuelan Oil Company) and University entities (national and international), was well recognized in Venezuela where I received a merit award by the Town Hall of Porlamar (Margarita Island).

• After graduation, I obtained a fellowship to enroll in a Master Degree program in Waste Management at the Universidad Internacional de Andalucia (Spain). My performance in this program allowed me to obtain a very prestigious Biomedicine fellowship (one awarded in all of Latin America) from the Santander-Central-Hispano Bank to begin a PhD in Genetics and Development related to Neuroscience at Universidad de Zaragoza (Spain).

• My PhD studies focused on comparative pathology, demonstrating pathology similar to Alzheimer's Disease in dogs and cetaceans. After a few years of work in academia in Venezuela, I obtained an opportunity to become a post-doctoral fellow at the University of Florida (USA).

• In 2014, I transferred to the Department of Neuroscience to work with Drs. David Borchelt. Since this time, my work has focused on understanding how mutations in Matrin 3 cause ALS and myopathy. In 2016, I was promoted to an entry level faculty position (Assistant Scientist) in the Department of Neuroscience and my goal includeded the use of techniques in genetics,, cellular biology and chemistry to develop a research program that spans basic science to pharmacological application in neuromuscular disorders.

Honors & Awards


  • Award of Merit “City of Porlamar”, Nueva Esparta State Government, Venezuela (2007)
  • Medal of Honor, Veterans Hospital-UNEFA (Department of Defense, Margarita Island, Venezuela) (2007)
  • PhD Genetics and Development, cum laude, Universidad de Zaragoza, Spain (2005)
  • MSc. Waste Management, cum laude, Universidad Internacional de Andalucia, Spain (2003)
  • BSc. Marine Biology, cum laude, Universidad de Oriente, Venezuela (1999)

Education & Certifications


  • PhD Genetics & Dev cum laude, Universidad de Zaragoza, (Zaragoza, Spain), Genetics (2005)
  • MSc. Waste Management cum laude, Universidad Internacional de Andalucia (Jaen, Spain), waste control (2004)
  • BSc. Marine Biology cum laude, Universidad de Oriente (Margarita Island, Venezuela), Biology (1999)

Publications

All Publications


  • N-terminal sequences in matrin 3 mediate phase separation into droplet-like structures that recruit TDP43 variants lacking RNA binding elements. Laboratory investigation; a journal of technical methods and pathology Gallego-Iradi, M. C., Strunk, H., Crown, A. M., Davila, R., Brown, H., Rodriguez-Lebron, E., Borchelt, D. R. 2019

    Abstract

    RNA binding proteins associated with amyotrophic lateral sclerosis (ALS) and muscle myopathy possess sequence elements that are low in complexity, or bear resemblance to yeast prion domains. These sequence elements appear to mediate phase separation into liquid-like membraneless organelles. Using fusion proteins of matrin 3 (MATR3) to yellow fluorescent protein (YFP), we recently observed that deletion of the second RNA recognition motif (RRM2) caused the protein to phase separate and form intranuclear liquid-like droplets. Here, we use fusion constructs of MATR3, TARDBP43 (TDP43) and FUS with YFP or mCherry to examine phase separation and protein colocalization in mouse C2C12 myoblast cells. We observed that the N-terminal 397 amino acids of MATR3 (tagged with a nuclear localization signal and expressed as a fusion protein with YFP) formed droplet-like structures within nuclei. Introduction of the myopathic S85C mutation into NLS-N397 MATR3:YFP, but not ALS mutations F115C or P154S, inhibited droplet formation. Further, we analyzed interactions between variants of MATR3 lacking RRM2 (ΔRRM2) and variants of TDP43 with disabling mutations in its RRM1 domain (deletion or mutation). We observed that MATR3:YFP ΔRRM2 formed droplets that appeared to recruit the TDP43 RRM1 mutants. Further, coexpression of the NLS-397 MATR3:YFP construct with a construct that encodes the prion-like domain of TDBP43 produced intranuclear droplet-like structures containing both proteins. Collectively, our studies show that N-terminal sequences in MATR3 can mediate phase separation into intranuclear droplet-like structures that can recruit TDP43 under conditions of low RNA binding.

    View details for DOI 10.1038/s41374-019-0260-7

    View details for PubMedID 31019288

  • Characterization of gene regulation and protein interaction networks for Matrin 3 encoding mutations linked to amyotrophic lateral sclerosis and myopathy SCIENTIFIC REPORTS Iradi, M., Triplett, J. C., Thomas, J. D., Davila, R., Crown, A. M., Brown, H., Lewis, J., Swanson, M. S., Xu, G., Rodriguez-Lebron, E., Borchelt, D. R. 2018; 8: 4049

    Abstract

    To understand how mutations in Matrin 3 (MATR3) cause amyotrophic lateral sclerosis (ALS) and distal myopathy, we used transcriptome and interactome analysis, coupled with microscopy. Over-expression of wild-type (WT) or F115C mutant MATR3 had little impact on gene expression in neuroglia cells. Only 23 genes, expressed at levels of >100 transcripts showed ≥1.6-fold changes in expression by transfection with WT or mutant MATR3:YFP vectors. We identified ~123 proteins that bound MATR3, with proteins associated with stress granules and RNA processing/splicing being prominent. The interactome of myopathic S85C and ALS-variant F115C MATR3 were virtually identical to WT protein. Deletion of RNA recognition motif (RRM1) or Zn finger motifs (ZnF1 or ZnF2) diminished the binding of a subset of MATR3 interacting proteins. Remarkably, deletion of the RRM2 motif caused enhanced binding of >100 hundred proteins. In live cells, MATR3 lacking RRM2 (ΔRRM2) formed intranuclear spherical structures that fused over time into large structures. Our findings in the cell models used here suggest that MATR3 with disease-causing mutations is not dramatically different from WT protein in modulating gene regulation or in binding to normal interacting partners. The intra-nuclear localization and interaction network of MATR3 is strongly modulated by its RRM2 domain.

    View details for DOI 10.1038/s41598-018-21371-4

    View details for Web of Science ID 000426643600013

    View details for PubMedID 29511296

    View details for PubMedCentralID PMC5840295

  • Alzheimer's disease in humans and other animals: A consequence of postreproductive life span and longevity rather than aging ALZHEIMERS & DEMENTIA Gunn-Moore, D., Kaidanovich-Beilin, O., Iradi, M., Gunn-Moore, F., Lovestone, S. 2018; 14 (2): 195–204

    Abstract

    Alzheimer's disease and diabetes mellitus are linked by epidemiology, genetics, and molecular pathogenesis. They may also be linked by the remarkable observation that insulin signaling sets the limits on longevity. In worms, flies, and mice, disrupting insulin signaling increases life span leading to speculation that caloric restriction might extend life span in man. It is our contention that man is already a long-lived organism, specifically with a remarkably high postfertility life span, and that it is this that results in the prevalence of Alzheimer's disease and diabetes.We review evidence for this hypothesis that carries specific predictions including that other animals with exceptionally long postreproductive life span will have increased risk of both diabetes and Alzheimer's disease.We present novel evidence that Dolphin, like man, an animal with exceptional longevity, might be one of the very few natural models of Alzheimer's disease.

    View details for DOI 10.1016/j.jalz.2017.08.014

    View details for Web of Science ID 000424405500009

    View details for PubMedID 28972881

  • Heterogeneity of Matrin 3 in the Developing and Aging Murine Central Nervous System JOURNAL OF COMPARATIVE NEUROLOGY Rayaprolu, S., D'Alton, S., Crosby, K., Moloney, C., Howard, J., Duffy, C., Cabrera, M., Siemienski, Z., Hernandez, A. R., Gallego-Iradi, C., Borchelt, D. R., Lewis, J. 2016; 524 (14): 2740–52

    Abstract

    Mutations in the MATR3 gene encoding the nucleotide binding protein Matrin 3 have recently been identified as causing a subset of familial amyotrophic lateral sclerosis (fALS) and more rarely causing distal myopathy. Translating the identification of MATR3 mutations into an understanding of disease pathogenesis and the creation of mouse models requires a complete understanding of normal Matrin 3 levels and distribution in vivo. Consequently, we examined the levels of murine Matrin 3 in body tissues and regions of the central nervous system (CNS). We observed a significant degree of variability in Matrin 3 protein levels among different tissues of adult animals, with the highest levels found in reproductive organs and the lowest in muscle. Within the adult CNS, Matrin 3 levels were lowest in spinal cord. Further, we found that Matrin 3 declines significantly in CNS through early development and young adulthood before stabilizing. As previously reported, antibodies to Matrin 3 primarily stain nuclei, but the intensity of staining was not uniform in all nuclei. The low levels of Matrin 3 in spinal cord and muscle could mean that that these tissues are particularly vulnerable to alterations in Matrin 3 function. Our study is the first to characterize endogenous Matrin 3 in rodents across the lifespan, providing the groundwork for deciphering disease mechanisms and developing mouse models of MATR3-linked ALS. J. Comp. Neurol. 524:2740-2752, 2016. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/cne.23986

    View details for Web of Science ID 000382547400002

    View details for PubMedID 26878116

    View details for PubMedCentralID PMC5832027

  • Subcellular Localization of Matrin 3 Containing Mutations Associated with ALS and Distal Myopathy PLOS ONE Gallego-Iradi, M., Clare, A. M., Brown, H. H., Janus, C., Lewis, J., Borchelt, D. R. 2015; 10 (11): e0142144

    Abstract

    Mutations in Matrin 3 [MATR3], an RNA- and DNA-binding protein normally localized to the nucleus, have been linked to amyotrophic lateral sclerosis (ALS) and distal myopathies. In the present study, we have used transient transfection of cultured cell lines to examine the impact of different disease-causing mutations on the localization of Matrin 3 within cells.Using CHO and human H4 neuroglioma cell models, we find that ALS/myopathy mutations do not produce profound changes in the localization of the protein. Although we did observe variable levels of Matrin 3 in the cytoplasm either by immunostaining or visualization of fluorescently-tagged protein, the majority of cells expressing either wild-type (WT) or mutant Matrin 3 showed nuclear localization of the protein. When cytoplasmic immunostaining, or fusion protein fluorescence, was seen in the cytoplasm, the stronger intensity of staining or fluorescence was usually evident in the nucleus. In ~80% of cells treated with sodium arsenite (Ars) to induce cytoplasmic stress granules, the nuclear localization of WT and F115C mutant Matrin 3 was not disturbed. Notably, over-expression of mutant Matrin 3 did not induce the formation of obvious large inclusion-like structures in either the cytoplasm or nucleus.Our findings indicate that mutations in Matrin 3 that are associated with ALS and myopathy do not dramatically alter the normal localization of the protein or readily induce inclusion formation.

    View details for DOI 10.1371/journal.pone.0142144

    View details for Web of Science ID 000364032600108

    View details for PubMedID 26528920

    View details for PubMedCentralID PMC4631352

  • KCNC3(R420H), a K+ channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking NEUROBIOLOGY OF DISEASE Gallego-Iradi, C., Bickford, J. S., Khare, S., Hall, A., Nick, J. A., Salmasinia, D., Wawrowsky, K., Bannykh, S., Huynh, D. P., Rincon-Limas, D. E., Pulst, S. M., Nick, H. S., Fernandez-Funez, P., Waters, M. F. 2014; 71: 270–79

    Abstract

    Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.

    View details for DOI 10.1016/j.nbd.2014.08.020

    View details for Web of Science ID 000342549900026

    View details for PubMedID 25152487

    View details for PubMedCentralID PMC4181561

  • CLONING, SEQUENCING AND EXPRESSION IN THE DOG OF THE MAIN AMYLOID PRECURSOR PROTEIN ISOFORMS AND SOME OF THE ENZYMES RELATED WITH THEIR PROCESSING NEUROSCIENCE Sarasa, L., Gallego, C., Monleon, I., Olvera, A., Canudas, J., Montanes, M., Pesini, P., Sarasa, M. 2010; 171 (4): 1091–1101

    Abstract

    Alzheimer's disease (AD) is characterized by neuronal loss and the presence of both neurofibrillary tangles and senile plaques in the brain. These plaques arise from the deposition of beta-amyloid (Aβ) peptides (38-43 amino acids), which are generated from enzymatic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In the present work, we cloned the principal APP isoforms as well as some enzymes that have been implicated in their amyloidogenic and non-amyloidogenic processing in dogs. Additionally, the main proteases implicated in the degradation of Aβ were also studied. We also investigated the level of expression of these APP isoforms and enzymes in different brain regions and in peripheral tissues. Our data demonstrate that these canine proteins are highly homologous to their human counterparts. In addition, the expression pattern of these proteins in dogs is consistent with previous data reported in human beings. Thus, dogs may be a natural model to study the biology of AD and could also serve as an animal model for Aβ-targeted drugs against this devastating disease.

    View details for DOI 10.1016/j.neuroscience.2010.09.042

    View details for Web of Science ID 000285231000011

    View details for PubMedID 20875843