Bio

Professional Education


  • Doctor of Philosophy, Leiden University (2011)

Stanford Advisors


Community and International Work


  • Stanford University Postdoctoral Association, Stanford

    Topic

    Enriching the postdoc experience at Stanford

    Populations Served

    Postdocs

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Molecular mechanisms underlying neuromuscular disorders and the molecular regulation of satellite cell quiescence and activation in relation to normal aging.

Publications

All Publications


  • Dysferlin regulates cell adhesion in human monocytes. journal of biological chemistry de MorrĂ©e, A., Flix, B., Bagaric, I., Wang, J., van den Boogaard, M., Grand Moursel, L., Frants, R. R., Illa, I., Gallardo, E., Toes, R., van der Maarel, S. M. 2013; 288 (20): 14147-14157

    Abstract

    Dysferlin is mutated in a group of muscular dystrophies commonly referred to as dysferlinopathies. It is highly expressed in skeletal muscle, where it is important for sarcolemmal maintenance. Recent studies show that dysferlin is also expressed in monocytes. Moreover, muscle of dysferlinopathy patients is characterized by massive immune cell infiltrates, and dysferlin-negative monocytes were shown to be more aggressive and phagocytose more particles. This suggests that dysferlin deregulation in monocytes might contribute to disease progression, but the molecular mechanism is unclear. Here we show that dysferlin expression is increased with differentiation in human monocytes and the THP1 monocyte cell model. Freshly isolated monocytes of dysferlinopathy patients show deregulated expression of fibronectin and fibronectin-binding integrins, which is recapitulated by transient knockdown of dysferlin in THP1 cells. Dysferlin forms a protein complex with these integrins at the cell membrane, and its depletion impairs cell adhesion. Moreover, patient macrophages show altered adhesion and motility. These findings suggest that dysferlin is involved in regulating cellular interactions and provide new insight into dysferlin function in inflammatory cells.

    View details for DOI 10.1074/jbc.M112.448589

    View details for PubMedID 23558685

  • Self-regulated alternative splicing at the AHNAK locus FASEB JOURNAL de Morree, A., Droog, M., Moursel, L. G., Bisschop, I. J., Impagliazzo, A., Frants, R. R., Klooster, R., van der Maarel, S. M. 2012; 26 (1): 93-103

    Abstract

    AHNAK is a 700-kDa protein involved in cytoarchitecture and calcium signaling. It is secondarily reduced in muscle of dysferlinopathy patients and accumulates in muscle of calpainopathy patients, both affected by a muscular dystrophy. AHNAK directly interacts with dysferlin. This interaction is lost on cleavage of AHNAK by the protease calpain 3, explaining the molecular observations in patients. Currently, little is known of AHNAK regulation. We describe the self-regulation of multiple mRNA transcripts emanating from the AHNAK locus in muscle cells. We show that the AHNAK gene consists of a 17-kb exon flanked by multiple small exons. This genetic structure is shared by AHNAK2 and Periaxin, which share a common ancestor. Two major AHNAK transcripts are differentially expressed during muscle differentiation that encode for a small (17-kDa) and a large (700-kDa) protein isoform. These proteins interact in the cytoplasm, but the small AHNAK is also present in the nucleus. During muscle differentiation the small AHNAK is strongly increased, thereby establishing a positive feedback loop to regulate mRNA splicing of its own locus. A small 17-kDa isoform of Periaxin similarly traffics between the cytoplasm and the nucleus to regulate mRNA splicing. Thus, AHNAK constitutes a novel mechanism in post-transcriptional control of gene expression.

    View details for DOI 10.1096/fj.11-187971

    View details for Web of Science ID 000299202200011

    View details for PubMedID 21940993

  • Proteomic Analysis of the Dysferlin Protein Complex Unveils Its Importance for Sarcolemmal Maintenance and Integrity PLOS ONE de Morree, A., Hensbergen, P. J., van Haagen, H. H., Dragan, I., Deelder, A. M., 't Hoen, P. A., Frants, R. R., van der Maarel, S. M. 2010; 5 (11)

    Abstract

    Dysferlin is critical for repair of muscle membranes after damage. Mutations in dysferlin lead to a progressive muscular dystrophy. Recent studies suggest additional roles for dysferlin. We set out to study dysferlin's protein-protein interactions to obtain comprehensive knowledge of dysferlin functionalities in a myogenic context. We developed a robust and reproducible method to isolate dysferlin protein complexes from cells and tissue. We analyzed the composition of these complexes in cultured myoblasts, myotubes and skeletal muscle tissue by mass spectrometry and subsequently inferred potential protein functions through bioinformatics analyses. Our data confirm previously reported interactions and support a function for dysferlin as a vesicle trafficking protein. In addition novel potential functionalities were uncovered, including phagocytosis and focal adhesion. Our data reveal that the dysferlin protein complex has a dynamic composition as a function of myogenic differentiation. We provide additional experimental evidence and show dysferlin localization to, and interaction with the focal adhesion protein vinculin at the sarcolemma. Finally, our studies reveal evidence for cross-talk between dysferlin and its protein family member myoferlin. Together our analyses show that dysferlin is not only a membrane repair protein but also important for muscle membrane maintenance and integrity.

    View details for DOI 10.1371/journal.pone.0013854

    View details for Web of Science ID 000283839100011

    View details for PubMedID 21079765

  • Calpain 3 Is a Rapid-Action, Unidirectional Proteolytic Switch Central to Muscle Remodeling PLOS ONE de Morree, A., Hulsik, D. L., Impagliazzo, A., van Haagen, H. H., de Galan, P., van Remoortere, A., 't Hoen, P. A., van Ommen, G. B., Frants, R. R., van der Maarel, S. M. 2010; 5 (8)

    Abstract

    Calpain 3 (CAPN3) is a cysteine protease that when mutated causes Limb Girdle Muscular Dystrophy 2A. It is thereby the only described Calpain family member that genetically causes a disease. Due to its inherent instability little is known of its substrates or its mechanism of activity and pathogenicity. In this investigation we define a primary sequence motif underlying CAPN3 substrate cleavage. This motif can transform non-related proteins into substrates, and identifies >300 new putative CAPN3 targets. Bioinformatic analyses of these targets demonstrate a critical role in muscle cytoskeletal remodeling and identify novel CAPN3 functions. Among the new CAPN3 substrates are three E3 SUMO ligases of the Protein Inhibitor of Activated Stats (PIAS) family. CAPN3 can cleave PIAS proteins and negatively regulates PIAS3 sumoylase activity. Consequently, SUMO2 is deregulated in patient muscle tissue. Our study thus uncovers unexpected crosstalk between CAPN3 proteolysis and protein sumoylation, with strong implications for muscle remodeling.

    View details for DOI 10.1371/journal.pone.0011940

    View details for Web of Science ID 000280574300008

    View details for PubMedID 20694146

  • Novel Protein-Protein Interactions Inferred from Literature Context PLOS ONE van Haagen, H. H., 't Hoen, P. A., Bovo, A. B., de Morree, A., van Mulligen, E. M., Chichester, C., Kors, J. A., den Dunnen, J. T., van Ommen, G. B., Van der Maarel, S. M., Kern, V. M., Mons, B., Schuemie, M. J. 2009; 4 (11)

    Abstract

    We have developed a method that predicts Protein-Protein Interactions (PPIs) based on the similarity of the context in which proteins appear in literature. This method outperforms previously developed PPI prediction algorithms that rely on the conjunction of two protein names in MEDLINE abstracts. We show significant increases in coverage (76% versus 32%) and sensitivity (66% versus 41% at a specificity of 95%) for the prediction of PPIs currently archived in 6 PPI databases. A retrospective analysis shows that PPIs can efficiently be predicted before they enter PPI databases and before their interaction is explicitly described in the literature. The practical value of the method for discovery of novel PPIs is illustrated by the experimental confirmation of the inferred physical interaction between CAPN3 and PARVB, which was based on frequent co-occurrence of both proteins with concepts like Z-disc, dysferlin, and alpha-actinin. The relationships between proteins predicted by our method are broader than PPIs, and include proteins in the same complex or pathway. Dependent on the type of relationships deemed useful, the precision of our method can be as high as 90%. The full set of predicted interactions is available in a downloadable matrix and through the webtool Nermal, which lists the most likely interaction partners for a given protein. Our framework can be used for prioritizing potential interaction partners, hitherto undiscovered, for follow-up studies and to aid the generation of accurate protein interaction maps.

    View details for DOI 10.1371/journal.pone.0007894

    View details for Web of Science ID 000271936700024

    View details for PubMedID 19924298

  • Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle HUMAN MOLECULAR GENETICS Huang, Y., de Morree, A., van Remoortere, A., Bushby, K., Frants, R. R., Dunnen, J. T., van der Maarel, S. M. 2008; 17 (12): 1855-1866

    Abstract

    Muscular dystrophies comprise a genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and weakness. Two forms of limb-girdle muscular dystrophy, 2A and 2B, are caused by mutations in calpain 3 (CAPN3) and dysferlin (DYSF), respectively. While CAPN3 may be involved in sarcomere remodeling, DYSF is proposed to play a role in membrane repair. The coexistence of CAPN3 and AHNAK, a protein involved in subsarcolemmal cytoarchitecture and membrane repair, in the dysferlin protein complex and the presence of proteolytic cleavage fragments of AHNAK in skeletal muscle led us to investigate whether AHNAK can act as substrate for CAPN3. We here demonstrate that AHNAK is cleaved by CAPN3 and show that AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients. Moreover, we demonstrate that AHNAK fragments cleaved by CAPN3 have lost their affinity for dysferlin. Thus, our findings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex.

    View details for DOI 10.1093/hmg/ddn081

    View details for Web of Science ID 000256275600017

    View details for PubMedID 18334579

  • GREG cells, a dysferlin-deficient myogenic mouse cell line EXPERIMENTAL CELL RESEARCH Humphrey, G. W., Mekhedov, E., Blank, P. S., de Morree, A., Pekkurnaz, G., Nagaraju, K., Zimmerberg, J. 2012; 318 (2): 127-135

    Abstract

    The dysferlinopathies (e.g. LGMD2b, Myoshi myopathy) are progressive, adult-onset muscle wasting syndromes caused by mutations in the gene coding for dysferlin. Dysferlin is a large (~200kDa) membrane-anchored protein, required for maintenance of plasmalemmal integrity in muscle fibers. To facilitate analysis of dysferlin function in muscle cells, we have established a dysferlin-deficient myogenic cell line (GREG cells) from the A/J mouse, a genetic model for dysferlinopathy. GREG cells have no detectable dysferlin expression, but proliferate normally in growth medium and fuse into functional myotubes in differentiation medium. GREG myotubes exhibit deficiencies in plasma membrane repair, as measured by laser wounding in the presence of FM1-43 dye. Under the wounding conditions used, the majority (~66%) of GREG myotubes lack membrane repair capacity, while no membrane repair deficiency was observed in dysferlin-normal C2C12 myotubes, assayed under the same conditions. We discuss the possibility that the observed heterogeneity in membrane resealing represents genetic compensation for dysferlin deficiency.

    View details for DOI 10.1016/j.yexcr.2011.10.004

    View details for Web of Science ID 000297902800004

    View details for PubMedID 22020321

  • Comparison of Dysferlin Expression in Human Skeletal Muscle with That in Monocytes for the Diagnosis of Dysferlin Myopathy PLOS ONE Gallardo, E., de Luna, N., Diaz-Manera, J., Rojas-Garcia, R., Gonzalez-Quereda, L., Flix, B., de Morree, A., van der Maarel, S., Illa, I. 2011; 6 (12)

    Abstract

    Dysferlinopathies are caused by mutations in the dysferlin gene (DYSF). Diagnosis is complex due to the high clinical variability of the disease and because dysferlin expression in the muscle biopsy may be secondarily reduced due to a primary defect in some other gene. Dysferlin is also expressed in peripheral blood monocytes (PBM). Studying dysferlin in monocytes is used for the diagnosis of dysferlin myopathies. The aim of the study was to determine whether dysferlin expression in PBM correlates with that in skeletal muscle.Using western-blot (WB) we quantified dysferlin expression in PBM from 21 pathological controls with other myopathies in whom mutations in DYSF were excluded and from 17 patients who had dysferlinopathy and two mutations in DYSF. Results were compared with protein expression in muscle by WB and immunohistochemistry (IH). We found a good correlation between skeletal muscle and monocytes using WB. However, IH results were misleading because abnormal expression of dysferlin was also observed in 13/21 pathological controls.The analysis of dysferlin protein expression in PBM is helpful when: 1) the skeletal muscle IH pattern is abnormal or 2) when muscle WB can not be performed either because muscle sample is lacking or insufficient or because the muscle biopsy is taken from a muscle at an end-stage and it mainly consists of fat and fibrotic tissue.

    View details for DOI 10.1371/journal.pone.0029061

    View details for Web of Science ID 000298664400035

    View details for PubMedID 22194990

  • In silico discovery and experimental validation of new protein-protein interactions PROTEOMICS van Haagen, H. H., 't Hoen, P. A., de Morree, A., van Roon-Mom, W. M., Peters, D. J., Roos, M., Mons, B., van Ommen, G., Schuemie, M. J. 2011; 11 (5): 843-853

    Abstract

    We introduce a framework for predicting novel protein-protein interactions (PPIs), based on Fisher's method for combining probabilities of predictions that are based on different data sources, such as the biomedical literature, protein domain and mRNA expression information. Our method compares favorably to our previous method based on text-mining alone and other methods such as STRING. We evaluated our algorithms through the prediction of experimentally found protein interactions underlying Muscular Dystrophy, Huntington's Disease and Polycystic Kidney Disease, which had not yet been recorded in protein-protein interaction databases. We found a 1.74-fold increase in the mean average prediction precision for dysferlin and a 3.09-fold for huntingtin when compared to STRING. The top 10 of predicted interaction partners of huntingtin were analysed in depth. Five were identified previously, and the other five were new potential interaction partners. The full matrix of human protein pairs and their prediction scores are available for download. Our framework can be extended to predict other types of relationships such as proteins in a complex, pathway or related disease mechanisms.

    View details for DOI 10.1002/pmic.201000398

    View details for Web of Science ID 000288137300002

    View details for PubMedID 21280221

  • Insect lipoprotein biogenesis depends on an amphipathic beta cluster in apolipophorin II/I and is stimulated by microsomal triglyceride transfer protein JOURNAL OF LIPID RESEARCH Smolenaars, M. M., de Morree, A., Kerver, J., Van der Horst, D. J., Rodenburg, K. W. 2007; 48 (9): 1955-1965

    Abstract

    Lipoproteins transport lipids in the circulation of an evolutionally wide diversity of animals. The pathway for lipoprotein biogenesis has been revealed to a large extent in mammals only, in which apolipoprotein B (apoB) acquires lipids via the assistance of microsomal triglyceride transfer protein (MTP) and binds them by means of amphipathic protein structures. To investigate whether this is a common mechanism for lipoprotein biogenesis in animals, we studied the structural elements involved in the assembly of the insect lipoprotein, lipophorin. LOCATE sequence analysis predicted that the insect lipoprotein precursor, apolipophorin II/I (apoLp-II/I), contains clusters of amphipathic alpha-helices and beta-strands, organized along the protein as N-alpha(1)-beta-alpha(2)-C, reminiscent of a truncated form of apoB. Recombinant expression of a series of C-terminal truncation variants of Locusta migratoria apoLp-II/I in an insect cell (Sf9) expression system revealed that the formation of a buoyant high density lipoprotein requires the amphipathic beta cluster. Coexpression of apoLp-II/I with the MTP homolog of Drosophila melanogaster affected insect lipoprotein biogenesis quantitatively as well as qualitatively, as the secretion of apoLp-II/I proteins was increased several-fold and the buoyant density of the secreted lipoprotein decreased concomitantly, indicative of augmented lipidation. Based on these findings, we propose that, despite specific modifications, the assembly of lipoproteins involves MTP as well as amphipathic structures in the apolipoprotein carrier, both in mammals and insects. Thus, lipoprotein biogenesis in animals appears to rely on structural elements that are of early metazoan origin.

    View details for DOI 10.1194/jlr.M600434-JLR200

    View details for Web of Science ID 000248792100006

    View details for PubMedID 17568063

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