In the largest genome-wide association study in ALS that included 15,000 ALS patients and 27,000 controls, we detected differences in 6 genome regions that lead to an increase in the risk of ALS. By using an innovative approach a new locus on the chromosome 21 was identified that contains a hitherto undiscovered gene C21orf2 that was associated with a high risk of an onset of ALS. Additionally, two more loci that are associated with a higher incidence of ALS, MOPB and SCFD1, were also identified. This indicates that ALS is a complex genetic trait with a polygenic architecture. This study represents a stepping-stone for further research that might identify additional targets and shed new light on the onset of this disease.
COBISS.SI-ID: 3106220
TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brainThe publication has been selected as an exceptional achievement of Slovenian science in the year 2011. Boris Rogelj shares the first authorship on this publication.
COBISS.SI-ID: 8278100
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. Dr. Rogelj shares the first authorship on this publication and currently has 1255 citations, which places it among the top 1% of the most highly cited compared to Medicine articles of same age and document type (Scopus). The publication is also in the 4th place of most highly cited in the field of neuroscience in the journal Science.
COBISS.SI-ID: 22877479
The paper describes unusual properties of cysteine carboxypeptidase cathepsin X in malignant processes. It presents molecular targets, degraded by this protease and mechanisms, leading to progression of the disease. Contrary to other lysosomal proteases cathepsin X does not degrade extracellular matrix but promote tumour progression through regulation of integrin receptors, gamma-enolase, chemokine CXCL-12, bradykinin, kallidin, huntingtin and profilin 1. In particular, its role is important when the activity of other proteases is inactivated, in particular of cathepsin B. In this case its expression is increased enabling alternative pathway of tumour proteolysis. This discovery is important if protease inhibitors are used in anti tumour therapy. The paper was selected for ARRS presentation "Excellent achievement in Science"
COBISS.SI-ID: 3650929
Cystatin F has been suggested to regulate the cytotoxicity of NK cells by inhibiting the major granzyme convertases, cathepsins C and H. To test this hypothesis, we prepared variants of cystatin F and analyzed their uptake, subcellular trafficking, peptidase inhibition, and the impact on the cytotoxicity of NK-92 cells and primary NK cells. We found that the glycosylation pattern is responsible for the secretion, uptake, and subcellular sorting of cystatin F. Active, N-terminally truncated, monomeric cystatin F can also be internalized by recipient cells and targeted to endo/lysosomes, affecting also cells lacking the activating peptidase. Cystatin F mutants capable of cell internalization and trafficking through the endo/lysosomal pathway significantly decreased cathepsin C and H activities, both in situ, following transfection and in trans, using conditioned media. Further, incubation of IL-2 stimulated NK-92 and primary NK cells with full-length and N-terminally truncated cystatin F mutants led to suppression of their granule-mediated cytotoxicity.
COBISS.SI-ID: 30930471
Gama-enolase is a neurotrophic-like factor promoting growth, differentiation, survival and regeneration of neurons. Its neurotrophic activity is regulated by cysteine protease cathepsin X which cleaves the C-terminal end of the molecule. We have investigated the expression and co-localization of gama-enolase and cathepsin X in brains of Tg2576 mice overexpressing amyloid precursor protein. Gamma enolase intact form, exhibiting neurotrophic activity, was observed in microglia cells in close proximity to senile plaque and was proved to be neuroprotective against Aß toxicity.
COBISS.SI-ID: 3441265
Cathepsin B been shown to be involved in cancer progression. We reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin and elucidated its anti-tumor properties in in vitro and in vivo tumor models. Nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment. Our results also designate nitroxoline as promising repositioning drug, available for registration for other indications.
COBISS.SI-ID: 3834225
Non-immunoglobulin (non-Ig) scaffolds are, in contrast to antibodies, small single-domain proteins that require no post-translational modification, often lack disulfide bonds, and can undergo straightforward multimerization. Among the 20 different types of non-Ig scaffolds, Adhirons, Alphabodies, Centyrins, Pronectins, Repebodies, Affimers, and Obodies have been introduced in the past 4 years. 102 proteins have been specifically targeted by 139 different non-Ig scaffold binders. The most frequent application of non-Ig scaffolds is in the treatment and diagnosis of cancer and inflammatory diseases, and 10 non-Ig scaffolds have already been tested in clinical trials.The achievement was published in Trends in Biotechnology, which is in the top 5% of journals in the field of Biotechnology and Applied Microbiology.
COBISS.SI-ID: 3851377
Identification of allergen epitopes is a key component in proper understanding of the pathogenesis of type I allergies, for understanding cross-reactivity and for the development of mimotope immunotherapeutics. Phage particles have gained recognition in the field of molecular allergology due to their value not only in competitive immunoscreening of peptide libraries but also as immunogenic carri- ers of allergen mimotopes. They integrate epitope discovery technology and immunization functions into a single platform. This article provides an overview of allergen mimotopes identified through the phage display technique. We discuss the most promising areas of mimotope application and the advantages and pitfalls of the methodology used to identify and validate the mimotopes.
COBISS.SI-ID: 4144497
To investigate the role of cathepsin X in the migration of T lymphocytes, Jurkat T cells were stably transfected with a pcDNA3 expression vector containing cathepsin X cDNA. The cathepsin-X-overexpressing T lymphocytes exhibited polarised migration-associated morphology, enhanced migration on 2D and 3D models and increased homotypic aggregation. We propose that cathepsin X causes cytoskeletal rearrangements and stimulates migration of T lymphocytes by modulating the activity of the beta2 integrin receptor LFA-1.
COBISS.SI-ID: 2370417