Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Stanslowsky, Nancy; Reinhardt, Peter; Glaß, Hannes; Kalmbach, Norman; Naujock, Maximilian; Hensel, Niko; Lübben, Verena; Pal, Arun; Venneri, Anna; Lupo, Fabio; Franceschi, Lucia De; Claus, Peter; Sterneckert, Jared; Storch, Alexander; Hermann, Andreas; Wegner, Florian

doi:10.1523/jneurosci.0456-16.2016

Cited by 42 publications

(67 citation statements)

References 66 publications

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“…Differentiation of SPNs was adapted from a previously published method . In brief, iPSCs were detached and resuspended in KSR medium to form embryoid bodies in low‐attachment plates.…”

Section: Methodsmentioning

confidence: 99%

“…We investigated whether the SVA retrotransposon insertion causes the reduction of TAF1 expression in XDP by using CRISPR/Cas9‐based genome editing to generate XDP cell lines with the SVA retrotransposon insertion excised. We performed the editing in iPSCs, which allows for later neural induction and further differentiation into distinct regional subtypes such as cortical and spiny projection neurons (SPNs) …”

mentioning

confidence: 99%

“…We performed the editing in iPSCs, which allows for later neural induction 9 and further differentiation into distinct regional subtypes such as cortical 10 and spiny projection neurons (SPNs). 11…”

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confidence: 99%

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Genome editing in induced pluripotent stem cells rescues TAF1 levels in X‐linked dystonia‐parkinsonism

et al. 2018

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(1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. © 2018 International Parkinson and Movement Disorder Society.

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“…Differentiation of SPNs was adapted from a previously published method . In brief, iPSCs were detached and resuspended in KSR medium to form embryoid bodies in low‐attachment plates.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Genome editing in induced pluripotent stem cells rescues TAF1 levels in X‐linked dystonia‐parkinsonism

et al. 2018

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“…In both erythrocytes and fibroblasts isolated from chorea-acanthocytosis patients, actin microfilaments are depolymerized [34, 44] (Fig. 1).…”

Section: Cytoskeletal Architecture Erythrocyte Shape and Endothelialmentioning

confidence: 99%

“…Accordingly, ORAI [56] and STIM [57] isoforms participate in the orchestration of survival, proliferation, and migration of tumor cells [70-73] and neural stem/progenitor cells [74]. In contrast to Ca 2+ oscillations, sustained [Ca 2+ ] i increases trigger apoptosis [42-44]. …”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

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Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca²⁺-channel accomplishing store operated Ca²⁺-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.

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Positive effect of Astragaloside IV on neurite outgrowth via talin‐dependent integrin signaling and microfilament force

Wang

Zhou

Tang

et al. 2020

Journal Cellular Physiology

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Integrin plays a prominent role in neurite outgrowth by transmitting both mechanical and chemical signals. Integrin expression is closely associated with Astragaloside IV (AS-IV), the main component extracted from Astragali radix, which has a positive effect on neural-protection. However, the relationship between AS-IV and neurite outgrowth has not been studied exhaustively to date. The present study investigated the underlying mechanism of AS-IV on neurite outgrowth. Longer neurites have been observed in SH-SY5Y cells or cortical neurons after AS-IV treatment. Furthermore, AS-IV not only increased the expression of integrin β but also activated it. The AS-IV-induced increased integrin activity was attributed to the integrin-activating protein talin. Application of the actin force probe showed that AS-IV led to an increase in intracellular microfilament force during neurite growth. Furthermore, in response to AS-IV, the microfilament force was regulated by talin and integrin activity during neurite growth. These results suggest that AS-IV has the ability to increase intracellular structural force and facilitate neurite elongation by integrin signaling, which highlights its therapeutic potential for neurite outgrowth.

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Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Cited by 42 publications

References 66 publications

Genome editing in induced pluripotent stem cells rescues TAF1 levels in X‐linked dystonia‐parkinsonism

Genome editing in induced pluripotent stem cells rescues TAF1 levels in X‐linked dystonia‐parkinsonism

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

Positive effect of Astragaloside IV on neurite outgrowth via talin‐dependent integrin signaling and microfilament force

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