The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

Ikiz, Burcin; Alvarez, Mariano J.; Ré, Diane B.; Verche, Virginia Le; Politi, Kristin A.; Lotti, Francesco; Phani, Sudarshan; Pradhan, Radhika; Yu, Changhao; Croft, Gist F.; Jacquier, Arnaud; Henderson, Christopher E.; Califano, Andrea; Przedborski, Serge

doi:10.1016/j.celrep.2015.06.019

Cited by 49 publications

(59 citation statements)

References 40 publications

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“…In addition, their use in non-cancer phenotypes has helped to elucidate an equivalent disease checkpoint architecture in neurological phenotypes — including amyotrophic lateral sclerosis (ALS) 53 , Alzheimer disease 7,54 , Parkinson disease 55 and alcohol addiction 56 — and in developmental phenotypes, from regulation of germinal centre formation 39 to stem cell pluripotency 57 . As briefly summarized below, these examples further outline the role of tumour checkpoint MRs in regulating disease dystasis and their unique nature compared with their physiological counterpart involved in homeostatic control.…”

Section: Mr and Tumour Checkpoint Elucidationmentioning

confidence: 99%

“…Postgenomic research has seen intense interest in the systematic dissection of the transcriptional and signalling logic of cancer cells (henceforth termed regulatory logic) 48,53,55–57 , including its transcriptional 58–60 , post-transcriptional 61–63 and post-translational 64–68 layers. These methods were first developed and validated in bacteria 69 and yeast 70,71 and then extended to mammalian cells 21,59 , thus complementing pre-existing literature-curated models 72 and large-scale experimental assays 73 .…”

Section: Mr and Tumour Checkpoint Elucidationmentioning

confidence: 99%

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The recurrent architecture of tumour initiation, progression and drug sensitivity

2016

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Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.

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Section: Mr and Tumour Checkpoint Elucidationmentioning

confidence: 99%

Section: Mr and Tumour Checkpoint Elucidationmentioning

confidence: 99%

The recurrent architecture of tumour initiation, progression and drug sensitivity

2016

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“…Indeed, virtually none of the regulators that were experimentally validated were significantly differentially expressed at the RNA level and yet they were confirmed as individual or synergistic phenotypic drivers following identification by regulatory network analysis, thus elucidating novel mechanisms of disease initiation/ progression [4,12,13,[41][42][43][44][45][46], chemosensitivity [15,28], and normal physiologic regulation [14]. Lately, we have successfully extended these methodologies to the study of neurological, neurodevelopmental, and stem cell phenotypes [35,42,47], and, more recently, to neurodegenerative phenotypes, resulting in a series of manuscripts, currently in review, where we report on the elucidation and experimental validation of novel genes mediating neurotoxicity in ALS [48], as well as biomarkers of AD progression [9].…”

Section: Creating the Assembly Manual Of The Alzheimer's Cellmentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

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In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

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“…Moreover, CD2 is not expressed in neural cells 21 , which were the target cells to purify. Importantly, cells expressing CD2 have not showed any detectable phenotypes when compared to parental lines 22 . Under the conditions established in this study, motoneurons were functionally mature after only 4 days of culture, as indicated by robust firing of APs (Figure 2C).…”

Section: Discussionmentioning

confidence: 98%

Bioreactor model of neuromuscular junction with electrical stimulation for pharmacological potency testing

et al. 2017

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In vitro models of the neuromuscular junction (NMJ) are emerging as a valuable tool to study synaptogenesis, synaptic maintenance, and pathogenesis of neurodegenerative diseases. Many models have previously been developed using a variety of cell sources for skeletal muscle and motoneurons. These models can advanced by integrating beneficial features of the native developmental milieu of the NMJ. We created a functional in vitro model of NMJ by bioreactor cultivation of transdifferentiated myocytes and stem cell-derived motoneurons, in the presence of electrical stimulation. In conjunction with a coculture medium, electrical stimulation resulted in improved maturation and function of motoneurons and myocytes, as evidenced by mature cellular structures, increased expression of neuronal and muscular genes, clusterization of acetylcholine receptors (AChRs) in the vicinity of motoneurons, and the response to glutamate stimulation. To validate the model and demonstrate its utility for pharmacological testing, we documented the potency of drugs that affect key pathways during NMJ signal transduction: (i) acetylcholine (ACh) synthesis, (ii) ACh vesicular storage, (iii) ACh synaptic release, (iv) AChR activation, and (v) ACh inactivation in the synaptic cleft. The model properly responded to the drugs in a concentration-dependent manner. We thus propose that this in vitro model of NMJ could be used as a platform in pharmacological screening and controlled studies of neuromuscular diseases.

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The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

Cited by 49 publications

References 40 publications

The recurrent architecture of tumour initiation, progression and drug sensitivity

The recurrent architecture of tumour initiation, progression and drug sensitivity

A Systems Approach to Drug Discovery in Alzheimer's Disease

Bioreactor model of neuromuscular junction with electrical stimulation for pharmacological potency testing

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