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Dissecting the role of REEP1 in preventing Tau-mediated neurodegeneration in a D.melanogaster Alzheimer's disease model
Alessio Guglielmi, 2019, doctoral dissertation

Abstract: Tau is natively an unfolded protein that promotes the assembly and the stability of the axonal microtubules in the central nervous system. Increased formation of Tau protein aggregates has been causatively implicated in several neurodegenerative diseases called tauopathies. In the present study, we used the Drosophila melanogaster system to express the longest isoform of human Tau (2N4R) in the nervous system of adult flies, recreating the main features of the human pathology. Herein, this Tau-mediated neurodegeneration model was used as a platform to perform genetic screenings to identify putative modifiers of Tau toxicity. Our strategy exploited the modulation of genes considered as risk factors of Alzheimer’s disease (AD), Frontotemporal Dementias and other neurodegenerative diseases by RNA interference in vivo. This approach allowed us to identify a new gene which participates in the neuronal response against Tau induced neurotoxicity in Drosophila: D-Reep1, homologue of human REEP1 gene (h-Reep1). D-Reep1 knockout flies showed no apparent phenotypes in physiological growing and developmental conditions, however, they showed peculiar sensitivity to stress conditions. In addition, D-Reep1 knockout enhanced the neurodegeneration mediated by Tau expression in Drosophila eyes. On the contrary, the overexpression of UAS-D-Reep1 and UAS-h-Reep1 abolished the typical rough eye phenotype induced by the presence of Tau. The Co-expression of D-Reep1 in Tau backgrounds did not alter the phosphorylation pattern of this protein while, the presence of D-Reep1 seemed to prevent the formation of Tau aggregates in vivo. Thus, the data support the idea that D-Reep1 exerts a protective role on Tau induced toxicity which is independent of its phosphorylation status. In this work, I analysed the mechanisms behind the neuroprotective role of D-Reep1 and, in particular, I found that REEP1 is involved in the regulation of the unfolded protein response (UPR) through the PERK-ATF4 cascade within the ER. By the activation of this pathway, the neurotoxic aggregates of Tau are removed from Drosophila neuronal tissues rescuing the normal characteristics of the affected tissues. Evidences also suggest that the activation of autophagy was behind the removal of Tau aggregates, providing new molecular information about the physiological role of D Reep1 in the nervous system.
Keywords: AD Alzheimer Disease APP Amyloid precursor protein CNS Central Nervous System DM Drosophila melanogaster HSP Hereditary Spastic Paraplegia LN Lewy’s neurite MT Microtubule MAP Microtubule associated protein MT Microtubule/s MTBD Microtubule binding domain NFT Neurofibrillary tangle NP Neuritic plaques PHF Paired helical filament PS1 Presenilin 1 PS2 Presenilin 2 SPG Spastic Paraplegia ThS Thioflavin S
Published in RUNG: 06.12.2019; Views: 2936; Downloads: 116
.pdf Full text (2,59 MB)

Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer’s disease
Dragan Gamberger, Nada Lavrač, Shantanu Srivatsa, Rudolph E. Tanzi, Murali Doraiswamy, 2017, original scientific article

Abstract: The heterogeneity of Alzheimer’s disease contributes to the high failure rate of prior clinical trials. We analyzed 5-year longitudinal outcomes and biomarker data from 562 subjects with mild cognitive impairment (MCI) from two national studies (ADNI) using a novel multilayer clustering algorithm. The algorithm identified homogenous clusters of MCI subjects with markedly different prognostic cognitive trajectories. A cluster of 240 rapid decliners had 2-fold greater atrophy and progressed to dementia at almost 5 times the rate of a cluster of 184 slow decliners. A classifier for identifying rapid decliners in one study showed high sensitivity and specificity in the second study. Characterizing subgroups of at risk subjects, with diverse prognostic outcomes, may provide novel mechanistic insights and facilitate clinical trials of drugs to delay the onset of AD.
Keywords: Alzheimer's disease, Rapid decliners, Data clustering, Mild cognitive impairment
Published in RUNG: 17.08.2017; Views: 3747; Downloads: 345
.pdf Full text (1,78 MB)

Outlier based literature exploration for cross-domain linking of Alzheimer's disease and gut microbiota
Donatella Gubiani, Elsa Fabbretti, Bojan Cestnik, Nada Lavrač, Tanja Urbančič, 2017, original scientific article

Abstract: In knowledge discovery, experts frequently need to combine knowledge from different domains to get new insights and derive new conclusions. Intelligent systems should support the experts in the search for relationships between concepts from different domains, where huge amounts of possible combinations require the systems to be efficient but also sufficiently general, open and interactive to enable the experts to creatively guide the discovery process. The paper proposes a cross-domain literature mining methodology that achieves this functionality by combining the functionality of two complementary text mining tools: clustering and topic ontology creation tool OntoGen and cross-domain bridging terms exploration tool CrossBee. Focusing on outlier documents identified by OntoGen contributes to the efficiency, while CrossBee allows for flexible and user-friendly bridging concepts exploration and identification. The proposed approach, which is domain independent and can support cross-domain knowledge discovery in any field of science, is illustrated on a biomedical case study dealing with Alzheimer’s dis- ease, one of the most threatening age-related diseases, deteriorating lives of numerous individuals and challenging the ageing society as a whole. By applying the proposed methodology to Alzheimer’s disease and gut microbiota PubMed articles, we have identified Nitric oxide synthase (NOS) as a potentially valuable link between these two domains. The results support the hypothesis of neuroinflammatory nature of Alzheimer’s disease, and is indicative for the quest for identifying strategies to control nitric oxide- associated pathways in the periphery and in the brain. By addressing common mediators of inflammation using literature-based discovery, we have succeeded to uncover previously unidentified molecular links between Alzheimer’s disease and gut microbiota with a multi-target therapeutic potential.
Keywords: Literature-based discovery, Outlier detection, Alzheimer's disease, Gut microbiome
Published in RUNG: 26.05.2017; Views: 4433; Downloads: 0
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