scholarly journals Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice

2021 ◽  
Vol 7 (14) ◽  
pp. eabb0799
Author(s):  
Amandine Virlogeux ◽  
Chiara Scaramuzzino ◽  
Sophie Lenoir ◽  
Rémi Carpentier ◽  
Morgane Louessard ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Wild Type ◽  
In Silico Screening ◽  
Survival Signaling ◽  
Locomotor Deficits ◽  
Induced Pluripotent ◽  
Network On A Chip

Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell–derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.

scholarly journals Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery

Brain ◽  
2013 ◽  
Vol 136 (12) ◽  
pp. 3561-3577 ◽  
Author(s):  
Daniel Tornero ◽  
Somsak Wattananit ◽  
Marita Grønning Madsen ◽  
Philipp Koch ◽  
James Wood ◽  
...  
Keyword(s):  
Stem Cell ◽  
Functional Recovery ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Characterization of the PLN p.Arg14del Mutation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2021 ◽  
Vol 22 (24) ◽  
pp. 13500
Author(s):  
Beatrice Badone ◽  
Carlotta Ronchi ◽  
Francesco Lodola ◽  
Anika E. Knaust ◽  
Arne Hansen ◽  
...  
Keyword(s):  
Functional Data ◽  
Pluripotent Stem Cell ◽  
Protein Localization ◽  
Induced Pluripotent Stem Cell ◽  
Wild Type ◽  
Time To Peak ◽  
Activation Mechanisms ◽  
Natural Inhibitor ◽  
Induced Pluripotent

Phospholamban (PLN) is the natural inhibitor of the sarco/endoplasmic reticulum Ca2+ ATP-ase (SERCA2a). Heterozygous PLN p.Arg14del mutation is associated with an arrhythmogenic dilated cardiomyopathy (DCM), whose pathogenesis has been attributed to SERCA2a “superinhibition”. Aim: To test in cardiomyocytes (hiPSC-CMs) derived from a PLN p.Arg14del carrier whether (1) Ca2+ dynamics and protein localization were compatible with SERCA2a superinhibition and (2) if functional abnormalities could be reverted by pharmacological SERCA2a activation (PST3093). Methods: Ca2+ transients (CaT) were recorded at 36 °C in hiPSC-CMs clusters during field stimulation. SERCA2a and PLN where immunolabeled in single hiPSC-CMs. Mutant preparations (MUT) were compared to isogenic wild-type ones (WT), obtained by mutation reversal. Results: WT and MUT differed for the following properties: (1) CaT time to peak (tpeak) and half-time of CaT decay were shorter in MUT; (2) several CaT profiles were identified in WT, “hyperdynamic” ones largely prevailed in MUT; (3) whereas tpeak rate-dependently declined in WT, it was shorter and rate-independent in MUT; (4) diastolic Ca2+ rate-dependently accumulated in WT, but not in MUT. When applied to WT, PST3093 turned all the above properties to resemble those of MUT; when applied to MUT, PST3093 had a smaller or negligible effect. Preferential perinuclear SERCA2a-PLN localization was lost in MUT hiPSC-CMs. Conclusions: Functional data converge to argue for PLN p.Arg14del incompetence in inhibiting SERCA2a in the tested case, thus weakening the rationale for therapeutic SERCA2a activation. Mechanisms alternative to SERCA2a superinhibition should be considered in the pathogenesis of DCM, possibly including dysregulation of Ca2+-dependent transcription.

scholarly journals Generation of induced pluripotent stem cell line, CSSi002-A (2851), from a patient with juvenile Huntington Disease

2018 ◽  
Vol 27 ◽  
pp. 86-89 ◽  
Author(s):  
Jessica Rosati ◽  
Eris Bidollari ◽  
Giovannina Rotundo ◽  
Daniela Ferrari ◽  
Barbara Torres ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Huntington Disease ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Line ◽  
Induced Pluripotent ◽  
Juvenile Huntington Disease

scholarly journals Generation of 5 induced pluripotent stem cell lines, LUMCi007-A and B and LUMCi008-A, B and C, from 2 patients with Huntington disease

2019 ◽  
Vol 39 ◽  
pp. 101498 ◽  
Author(s):  
Linda M. van der Graaf ◽  
Sarah L. Gardiner ◽  
Merve Tok ◽  
Tom Brands ◽  
Merel W. Boogaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lines ◽  
Huntington Disease ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Lines ◽  
Induced Pluripotent
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