Modeling Polyglutamine Expansion Diseases with Induced Pluripotent Stem Cells

Naphade, Swati; Tshilenge, Kizito-Tshitoko; Ellerby, Lisa M.

doi:10.1007/s13311-019-00810-8

Cited by 27 publications

(43 citation statements)

References 212 publications

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“…Creus-Muncunill and Ehrlich review the detailed and elegant studies directed at understanding the cellautonomous and non-autonomous pathogenic mechanisms in HD [14]. Naphade et al describe the rapid progress using human patient-induced pluripotent stem cells to model HD and other polyQ diseases [15].…”

Section: Spinal and Bulbar Muscular Atrophy/kennedy's Diseasementioning

confidence: 99%

Repeat Expansion Disorders: Mechanisms and Therapeutics

Ellerby

2019

Neurotherapeutics

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Section: Spinal and Bulbar Muscular Atrophy/kennedy's Diseasementioning

confidence: 99%

Repeat Expansion Disorders: Mechanisms and Therapeutics

Ellerby

2019

Neurotherapeutics

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“…Next, to increase the relevance of the current study, we moved forward and determined the possible effects of IGF2 in a human model of HD that do not rely on overexpression using induced pluripotent stem cells (iPSCs) derived from patients (31,32). Thus, we generated human medium spiny neurons (MSNs) using iPSC-derived from HD patients and control subjects ( Fig.…”

Section: Igf2 Reduces the Aggregation Of Expanded Polyglutamine Proteinsmentioning

confidence: 99%

Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

García-Huerta

Troncoso-Escudero

et al. 2020

Preprint

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One sentence summary: IGF2 reduces the load of intracellular protein aggregates through the extracellular disposal of the mutant protein. AbstractImpaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease-modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here we studied the impact of IGF2 signaling on protein aggregation in models of Huntington´s disease (HD) as proof-of-concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients.The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 were independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human post-mortem brain tissue, and blood samples from HD patients showed a reduction of IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein aggregates. tools to study IGF2 signaling. We thank Marioly Müller and Dr. Josefina Barrera and her team for their kind help taking the blood samples. We thank Dr. Felipe Oyarzun and Rodrigo Sierpe for the kindly help with the use of the Nanosight NS300. We specially acknowledge Carolina Jerez, Claudia Rivera, Valentina Castillo and Constanza Gonzalez for their technical assistance.

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“…Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common subtype of spinocerebellar ataxias (SCAs), accounting for about 60~70% of SCAs in Chinese population [1,2].The pathogenesis of SCA3/MJD is due to the abnormal CAG repeats in the encoding region of ATXN3. The normal CAG repeats expand from 11 to 44, when the dynamic expansions up to 60~87, disease occurred [3][4][5][6]. CAG expansions in SCA3/MJD inversely correlates with age at onset (AAO), contributing to 50~80% of the AAO variation, suggesting that modi er genes, epigenetics and other environmental factors also affect the AAO.…”

Section: Introductionmentioning

confidence: 99%

“…Unstable CAG expansions result in abnormal polyglutamine (polyQ) tract in ataxin-3 protein, forming neuronal intranuclear inclusions (NIIs) selectively accumulated in the cerebellum, brainstem, brain cortex, spinal cord, etc. Expanded polyQ protein affects various cellular activities via a gain of toxic functions, thus causing cell death [3]. Given that the pathogenesis of SCA3/MJD has not been elaborated completely, and no idea treatment methods have been achieved, it is urgent to study the pathogenic mechanism and explore new therapies of SCA3/MJD.…”

Section: Introductionmentioning

confidence: 99%

“…Human induced pluripotent stem cells (hiPSCs) carry the entire genetic background of patients and could be differentiated into unlimited source of interested cell populations. Increasingly, Cas9-directed genomeediting of iPSCs offers unprecedented opportunity for disease modeling, drug screening and cell replacement therapy for neurodegenerative diseases [3,33,34]. Previously, we obtained the urethral epithelial cells derived iPSCs from SCA3/MJD patients with 74/31 CAG repeats, which own the same mutant ATXN3 as parental somatic cells, and capable of differentiating into neuronal cells (NCs), providing an ideal cell models for studying the pathological mechanisms and drug screening of SCA3/MJD [35].…”

Section: Introductionmentioning

confidence: 99%

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CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

Wang

Zhao

et al. 2020

Preprint

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Background：Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive autosomal dominant neurodegenerative disease caused by abnormal CAG repeats in exon 10 of ATXN3. The accumulation of the mutant ataxin3 proteins carrying polyglutamine (polyQ) lead to selective degeneration of neurons. Therapeutic strategies were used to inhibit mutant ATXN3 expression, including antisense oligonucleotides, RNA interference and more recently CRISPR/Cas9 genome-editing based approaches. Since the pathogenesis of SCA3 has not been fully elucidated, and no effective therapies can be used, it is crucial to investigate the pathogenesis and seek new therapeutic strategies of SCA3/MJD. Methods: Here we used the paired sgRNA/Cas9 nickases and Cre-loxP mediated homologous recombination (HR) strategy to precisely modify the abnormal CAG expansions in the ATXN3 of SCA3/MJD patient derived induced pluripotent stem cells (SCA3/MJD-iPSCs). Meanwhile, we investigated the disease related phenotypes in differentiated neurons, including electrophysiological characteristics, IC2-positive aggregations, mitochondrial membrane potentials (MMPs), glutathione (GSH) expressions, intracellular reactive oxygen species (ROS), Ca2+ concentrations and malondialdehyde (MDA) levels. Results: SCA3/MJD-iPSCs can be corrected by the replacement of the abnormal CAG expansions with normal repeats using HR. Besides, corrected SCA3/MJD-iPSCs retained pluripotent and normal karyotype, which could be differentiated into neuron cells (NCs) and maintained electrophysiological characteristics. The expression of differentiation markers and electrophysiological characteristics were similar among the control individuals, SCA3/MJD patients and isogenic control SCA3/MJD groups. Furthermore, this study proved that the phenotypic abnormalities in SCA3/MJD-iPSCs derived NCs, including aggregated polyQ toxic protein, decreased MMPs and GSH expressions, increased ROS, Ca2+ concentrations and MDA levels, all were rescued in the corrected SCA3/MJD-NCs. Conclusion: The present study firstly suggested that the genetically corrected SCA3/MJD-iPSCs and associated phenotypic abnormalities, which will provide an ideal models for molecular mechanism research and autologous stem cell therapy.

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Modeling Polyglutamine Expansion Diseases with Induced Pluripotent Stem Cells

Cited by 27 publications

References 212 publications

Repeat Expansion Disorders: Mechanisms and Therapeutics

Repeat Expansion Disorders: Mechanisms and Therapeutics

Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

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Modeling Polyglutamine Expansion Diseases with Induced Pluripotent Stem Cells

Cited by 27 publications

References 212 publications

Repeat Expansion Disorders: Mechanisms and Therapeutics

Repeat Expansion Disorders: Mechanisms and Therapeutics

Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

CRISPR/Cas9&nbsp;Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD&nbsp;Disease Patient Derived Induced Pluripotent Stem Cells

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CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells