Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks

Canals, Isaac; Soriano, Jordi; Orlandi, Javier G.; Torrent, Roger; Richaud‐Patin, Yvonne; Jiménez‐Delgado, Senda; Merlin, Simone; Follenzi, Antonia; Consiglio, Antonella; Vilageliu, Lluı̈sa; Grinberg, Daniel

doi:10.1016/j.stemcr.2015.08.016

Cited by 32 publications

(58 citation statements)

References 44 publications

(65 reference statements)

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“…Another study reported that heparan sulfate oligosaccharides were able to increase the formation of focal adhesions in mouse astrocytes and human neural progenitor cells, leading to cell polarization and migration defects [142]. These data are in line with changes of neuronal organization, effective connectivity, and spontaneous activity detected in MPS IIIC patient iPSC-derived neuronal progenitors [143].…”

Section: Specific Effects Of Heparan Sulfatesupporting

confidence: 65%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Section: Specific Effects Of Heparan Sulfatesupporting

confidence: 65%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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“…We show an experimental application of our approach to spontaneously generated in vitro networks of human iPSC-derived neurons cultured on MEAs providing an analysis and interpretation of the physiology not possible otherwise. We describe the temporal evolution associated with the connectivity and dynamic signaling of developing hiPSC-derived neuronal networks, including increasing synchronized activity and the formation of small numbers of hyper-connected hub-like nodes, as similarly reported by others [14,20]. These results further support the performance quality of our approach and provide an example of how this connectivity method can be used to characterize network formation and dynamics, thus facilitating efforts to generate predictive models for neurological disease, drug discovery and neural network modeling.…”

Section: Figuresupporting

confidence: 53%

“…In humans, in the absence of intracranial recording electrodes, neither physiological nor pathological network activity can be studied in vivo. The introduction of human induced-pluripotent stem cell (hiPSC) technologies [12,13] opened the possibility to generate in-vitro neuronal networks in typical [14,15], as well as patient-specific genetic backgrounds [16,17,18,19,20,21], demonstrating the potential to reproduce key molecular and pathophysiological processes in highly controlled, reduced, experimental models that enables the study of neurological disorders and the discovery and testing of drugs, especially in the context of the individual patient [22,23,24].…”

Section: Introductionmentioning

confidence: 99%

Super-selective reconstruction of causal and direct connectivity with application toin-vitroiPSC neuronal networks

Puppo

PrÐ

Bang

et al. 2020

Preprint

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Despite advancements in the development of cell-based in-vitro neuronal network models, the lack of appropriate computational tools limits their analyses. Methods aimed at deciphering the effective connections between neurons from extracellular spike recordings would increase utility of in-vitro local neural circuits, especially for studies of human neural development and disease based on induced pluripotent stem cells (hiPSC). Current techniques allow statistical inference of functional couplings in the network but are fundamentally unable to correctly identify indirect and apparent connections between neurons, generating redundant maps with limited ability to model the causal dynamics of the network. In this paper, we describe a novel mathematically rigorous, model-free method to map effective -direct and causal -connectivity of neuronal networks from multi-electrode array data. The inference algorithm uses a combination of statistical and deterministic indicators which, first, enables identification of all existing functional links in the network and then, reconstructs the directed and causal connection diagram via a super-selective rule enabling highly accurate classification of direct, indirect and apparent links. Our method can be generally applied to the functional characterization of any in-vitro neuronal networks. Here, we show that, given its accuracy, it can offer important insights into the functional development of in-vitro iPSC-derived neuronal cultures by reconstructing their effective connectivity, thus facilitating future efforts to generate predictive models for neurological disorders, drug testing and neuronal network modeling.

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“…In Sanfilippo disease (mucopolysaccharidosis III), there is an accumulation of heparan sulfate in the lysosomes due to an impaired function of one of several lysosomal enzymes. We have assayed the inhibition of the EXTL2 and EXTL3 genes, as a substrate reduction therapy for Sanfilippo C disease in patients' fibroblasts and we are currently performing a similar approach on Sanfilippo C neurons, derived from induced pluripotent stem cells (iPSC) generated by our group …”

Section: Osteochondromatosis or Multiple Hereditary Exostosismentioning

confidence: 99%

“…Our aim was to create osteoblasts derived from WT human iPSC generated in our group and compare them with those generated from GD patients (N370S/N370S, a gift from Ricardo Feldman, G202R/L444P, a gift from Gustavo Tiscornia, and N370S/84GG). For the MSC‐like cell induction, we used a multistep culture method, summarized in Figure A.…”

Section: Gaucher Diseasementioning

confidence: 99%

Bone development and remodeling in metabolic disorders

Serra-Vinardell

Roca-Ayats

De-Ugarte

et al. 2019

J of Inher Metab Disea

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There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre‐existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

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Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks

Cited by 32 publications

References 44 publications

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Super-selective reconstruction of causal and direct connectivity with application toin-vitroiPSC neuronal networks

Bone development and remodeling in metabolic disorders

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