Signaling defects in iPSC-derived fragile X premutation neurons

Liu, Jing; Koscielska, Katarzyna Anna; Cao, Zhengyu; Hulsizer, Susan; Grace, Natalie; Mitchell, Gaela; Nacey, Catherine; Githinji, Jackline; McGee, Jeannine; Garcia-Arocena, Dolores; Hagerman, Randi J.; Nolta, Jan A.; Pessah, Isaac N.; Hagerman, Paul J.

doi:10.1093/hmg/dds207

Cited by 129 publications

(107 citation statements)

References 37 publications

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“…The recent advances in the use of iPSCs derived from human cells enable the testing of therapeutic strategies Bin a dish^ [225]. Early studies in FXS patient-derived iPSCs suggest that some FXS-associated defects are replicated in these cells [226][227][228], although the classic phenotypes reported in the mouse model, for example exaggerated protein synthesis and altered dendritic spine morphology, have yet to be examined in FXS iPSC-derived neurons. In the future, it will be important to identify robust phenotypes in human iPSCderived neurons from FXS that are suitable to test or screen for therapeutic drugs.…”

Section: Challenges and Future Outlook For Preclinical Studiesmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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Section: Challenges and Future Outlook For Preclinical Studiesmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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“…Although most image processing algorithms are used to analyse small stacks of in vitro recordings, 3D dendritic spine analysis has also been carried out in tissue slice cultures 87 and in vivo recordings 107 . Tracking the changes in dendritic spine density and morphology in living animals would not only allow real-time monitoring of the acute effects of drug treatments, but also enable direct correlation of neuronal connectivity parameters with cognitive and behavioural characteristics.Calcium imaging is a valuable tool in the emerging field of iPSC technology to characterize iPSC-derived neurons and to detect phenotypes in patient-derived cultures [108][109][110][111] . Although calcium imaging studies are mostly performed on monocultures, a direct extension of such experiments would be to shift to the co-cultivation of differentially labelled neuronal cultures.…”

Section: Discussionmentioning

confidence: 99%

Image Informatics Strategies for Deciphering Neuronal Network Connectivity

Detrez

Verstraelen

Gebuis

et al. 2016

Focus on Bio-Image Informatics

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Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphological plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular communication and the associated calcium-bursting behaviour. In vitro cultured neuronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies.2

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“…Highlighting its importance to neurodevelopment, lines that demonstrated reduced FRM1 expression resulted in aberrant neuronal differentiation [60]. Another study generated iPSC from FXS premutation individuals (carrying 55-200 CGG repeats), who do not display with classical FXS but suffer from neurodegenerative fragile X-associated tremor/ataxia syndrome [61,62]. Interestingly, neurons derived from these iPSCs revealed reduced neurite length, fewer synaptic puncta, reduced synaptic protein levels, and increased calcium stransients [61].…”

Section: Fxsmentioning

confidence: 99%

“…Another study generated iPSC from FXS premutation individuals (carrying 55-200 CGG repeats), who do not display with classical FXS but suffer from neurodegenerative fragile X-associated tremor/ataxia syndrome [61,62]. Interestingly, neurons derived from these iPSCs revealed reduced neurite length, fewer synaptic puncta, reduced synaptic protein levels, and increased calcium stransients [61]. A recent report showed that forebrain neurons derived from iPSCs from patients with FXS also showed reduced neurite outgrowth [63].…”

Section: Fxsmentioning

confidence: 99%

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment

Acab

Muotri

2015

Neurotherapeutics

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Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders sharing a core set of symptoms, including impaired social interaction, language deficits, and repetitive behaviors. While ASDs are highly heritable and demonstrate a clear genetic component, the cellular and molecular mechanisms driving ASD etiology remain undefined. The unavailability of live patient-specific neurons has contributed to the difficulty in studying ASD pathophysiology. The recent advent of induced pluripotent stem cells (iPSCs) has provided the ability to generate patient-specific human neurons from somatic cells. The iPSC field has quickly grown, as researchers have demonstrated the utility of this technology to model several diseases, especially neurologic disorders. Here, we review the current literature around using iPSCs to model ASDs, and discuss the notable findings, and the promise and limitations of this technology. The recent report of a nonsyndromic ASD iPSC model and several previous ASD models demonstrating similar results points to the ability of iPSC to reveal potential novel biomarkers and therapeutics.

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Signaling defects in iPSC-derived fragile X premutation neurons

Cited by 129 publications

References 37 publications

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Image Informatics Strategies for Deciphering Neuronal Network Connectivity

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment

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