Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation

Bogetofte, Helle; Jensen, Pia; Okarmus, Justyna; Schmidt, Sissel Ida; Agger, Mikkel; Ryding, Matias; Nørregaard, Peter; Fenger, Christina; Zeng, Xianmin; Graakjær, Jesper; Ryan, Brent J.; Wade‐Martins, Richard; Larsen, Martin R.; Meyer, Morten

doi:10.1016/j.nbd.2019.104581

Cited by 36 publications

(48 citation statements)

References 65 publications

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“…4a, c). It is important to note that the frequency of reported phenotypes in our meta-analysis may be biased because only few studies (~19%, 13/67) reported negative results (absence of phenotypes) 31,32,36,37,40,45,48,52,59,64,74,76,86 . In addition, most cell lines were not systematically phenotyped without prior hypothesis and thus, there is likely to be an ascertain bias in these phenotypes.…”

Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

“…In addition, most cell lines were not systematically phenotyped without prior hypothesis and thus, there is likely to be an ascertain bias in these phenotypes. Less hypothesis-driven multimodal or omics analysis will help to address such bias 41,72,[76][77][78][79][80]87,90 . Phenotypes caused by genomic predispositions allude to crosstalk and impairments in multiple pathways that act collectively to mediate selective degeneration of dopaminergic neurons in the substantia nigra ( Fig.…”

Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

“…Dysregulation of autophagy and protein ubiquitination contributes to neurodegeneration Across 15 hiPSC studies, evidence of impaired protein degradation in LRRK2, PRKN, GBA, DJ-1, SNCA, and sporadic PD lines has been reported 26,27,29,36,45,[48][49][50]53,56,58,63,69,75 . Unbiased pathway analysis of cysteine-modified proteins revealed an enrichment of proteins involved in the ubiquitination and removal of unfolded protein 76 . Accumulation of autophagosomes and increased expression of key autophagy regulators (i.e., beclin1, p62) were also consistently noted in PD neurons, suggestive of an upregulation of autophagy initiation 26,36,48,49,56,74 .…”

Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

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Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Tran

Anastacio

Bardy

2020

npj Parkinsons Dis.

120

103

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Parkinson's disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson's genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson's patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson's disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson's patients may guide future personalized drug screens in preclinical research.

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Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

Section: How Environmental Factors and Aging Can Be Recapitulated In mentioning

confidence: 99%

See 1 more Smart Citation

Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Tran

Anastacio

Bardy

2020

npj Parkinsons Dis.

120

103

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“…1. Neurons were generated using a previously described robust differentiation protocol (26,37). Differentiated cells were collected, and the metabolites were extracted for LC-MS analysis.…”

Section: Metabolomic Profiling Of Park2 Ko Neurons By Lc-msmentioning

confidence: 99%

Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism

Okarmus

Havelund

Ryding

et al. 2020

Preprint

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PARK2 (parkin) mutations cause early onset of autosomal recessively inherited Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase and has been reported to participate in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain largely unknown. Human induced pluripotent stem cells (iPSCs) with PARK2 knockout (KO) provide a valuable model for studying parkin dysfunction in dopaminergic neurons. In the current study, we used isogenic iPSCs to investigate the effect of parkin loss-of-function by comparative metabolomics analysis. The metabolomic profile of the PARK2 KO neurons differed substantially from that of healthy controls. We found increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure connected with ATP depletion, glycolysis dysregulation with lactate accumulation, and elevated levels of short- and long-chain carnitines. These mitochondrial and energy perturbations in the PARK2 KO neurons were combined with increased levels of oxidative stress and a decreased anti-oxidative response. In conclusion, our data describe a unique metabolomic profile associated with parkin dysfunction, demonstrating several PD-related cellular defects. Our findings support and expand previously described PD phenotypic features and show that combining metabolomic analysis with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.

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“…They characterized differences in MAPT splicing and tau PTMs, showing that A152T neurons had increasing levels of tau. Another group identified altered phosphorylation and cysteine modifications in the cytoskeleton and RhoA signaling proteins in dopaminergic neurons with loss of PARK2 [133]. Further, when comparing differentially expressed proteins in spinal muscular atrophy iPSC-derived motor neurons to their source fibroblasts, the iPSC-derived motor neurons had fewer proteins than controls, including proteins involved in viability (beta III-tubulin and UCHL1) and UBA1 involved in protein degradation signaling [134].…”

Section: Proteomic Analysis Of 2d Human Ipsc-derived Neuron Culturesmentioning

confidence: 99%

Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders

Murtaza

Singh

2020

Molecular Autism

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Proteomics is the large-scale study of the total protein content and their overall function within a cell through multiple facets of research. Advancements in proteomic methods have moved past the simple quantification of proteins to the identification of post-translational modifications (PTMs) and the ability to probe interactions between these proteins, spatially and temporally. Increased sensitivity and resolution of mass spectrometers and sample preparation protocols have drastically reduced the large amount of cells required and the experimental variability that had previously hindered its use in studying human neurological disorders. Proteomics offers a new perspective to study the altered molecular pathways and networks that are associated with autism spectrum disorders (ASD). The differences between the transcriptome and proteome, combined with the various types of post-translation modifications that regulate protein function and localization, highlight a novel level of research that has not been appropriately investigated. In this review, we will discuss strategies using proteomics to study ASD and other neurological disorders, with a focus on how these approaches can be combined with induced pluripotent stem cell (iPSC) studies. Proteomic analysis of iPSC-derived neurons have already been used to measure changes in the proteome caused by patient mutations, analyze changes in PTMs that resulted in altered biological pathways, and identify potential biomarkers. Further advancements in both proteomic techniques and human iPSC differentiation protocols will continue to push the field towards better understanding ASD disease pathophysiology. Proteomics using iPSC-derived neurons from individuals with ASD offers a window for observing the altered proteome, which is necessary in the future development of therapeutics against specific targets. Autism spectrum disorders

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Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation

Cited by 36 publications

References 65 publications

Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism

Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders

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