Reprogramming of a human induced pluripotent stem cell (iPSC) line (IBMSi012-A) from an early-onset Parkinson's disease patient harboring a homozygous p.D331Y mutation in the PLA2G6 gene

Cheng, Yu‐Che; Lin, Han-I; Syu, Shih-Han; Lu, Huai-En; Huang, Ching‐Ying; Lin, Chin-Hsien; Hsieh, Patrick C.H.

doi:10.1016/j.scr.2019.101432

Cited by 3 publications

(3 citation statements)

References 4 publications

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“…Abnormalities in the PLA2G6 gene are often manifested in various neurodegenerative diseases (Ji et al, 2019), such as infantile neuroaxonal dystrophy (INAD), atypical infantile neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive EOPD (Cheng et al, 2019). The mechanism of action may be associated with the D331Y and T572I mutations in the PLA2G6 domain, leading to the reduction of the formation of dopamine neurons and the manifestation of the neuromotor symptom phenotype (Yeh et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A case of PLA2G6 gene-related early-onset Parkinson's disease and review of literature

Gao

Shi

et al. 2022

Front. Neurosci.

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BackgroundEarly onset Parkinson's disease (EOPD) is a neurodegenerative disease associated with the action ofto genetic factors. A mutated phospholipase A2 type VI gene (PLA2G6) is considered to be one of pathogenic genes involved in EOPD development. Although EOPD caused by a mutated PLA2G6 has been recorded in major databases, not all mutant genotypes have been reported. Here, we report a case of PLA2G6-related EOPD caused by a novel compound heterozygous mutation.Case presentationThe case was an of 26-year-old young male with a 2-year course of disease. The onset of the disease was insidious and developed gradually. The patient presented with unsteady walking, bradykinesia, unresponsiveness, and decreased facial expression. Auxiliary examination showed a compound heterozygous mutation of the PLA2G6gene with c.991G > T and c.1427 + 1G > A. Mild atrophy of the cerebrum and cerebellum was detected on brain MRI. The patient was diagnosed with EOPD. We administered treatment with Madopar, which was effective. After a two-year disease course, we observed progression to stage 5 according to the Hoehn-Yahr Scale (without medicine in the off-stage). An MDS-UPDRS III score of 62 was obtained, with characteristics of severe disease and rapid progress. The diagnosis was an EOPD phenotype caused by a combination of mutations at the c.991G > T and c.1427 + 1G > A sites of the PLA2G6gene.ConclusionAfter active treatment, the disease was set under control, with no significant progression during the three-month follow-up period. Dyskinesia did not recur after reducing the Madopar dose. The freezing sign was slightly decreased and the wearing-off was delayed to 2 h.

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Section: Discussionmentioning

confidence: 99%

Case Report: A case of PLA2G6 gene-related early-onset Parkinson's disease and review of literature

Gao

Shi

et al. 2022

Front. Neurosci.

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“…This discovery has enabled the study of many diseases as these stem cell lines can be derived from patients suffering from different diseases and disorders. Using patient derived hiPSCs lines and differentiating them into a target tissue type is a powerful way to study diseases, including those affecting the nervous system -like Alzheimer's and Parkinson's (Playne and Connor, 2017;Cheng et al, 2018Cheng et al, , 2019Penney et al, 2019). Often, research on hiPSC models of these diseases is conducted in 2D, despite brain tissue possessing a complex 3D structure.…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinting Pluripotent Stem Cell Derived Neural Tissues Using a Novel Fibrin Bioink Containing Drug Releasing Microspheres

Sharma

Smits

Vega

et al. 2020

Front. Bioeng. Biotechnol.

110

104

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3D bioprinting combines cells with a supportive bioink to fabricate multiscale, multicellular structures that imitate native tissues. Here, we demonstrate how our novel fibrinbased bioink formulation combined with drug releasing microspheres can serve as a tool for bioprinting tissues using human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs). Microspheres, small spherical particles that generate controlled drug release, promote hiPSC differentiation into dopaminergic neurons when used to deliver small molecules like guggulsterone. We used the microfluidics based RX1 bioprinter to generate domes with a 1 cm diameter consisting of our novel fibrin-based bioink containing guggulsterone microspheres and hiPSC-derived NPCs. The resulting tissues exhibited over 90% cellular viability 1 day post printing that then increased to 95% 7 days post printing. The bioprinted tissues expressed the early neuronal marker, TUJ1 and the early midbrain marker, Forkhead Box A2 (FOXA2) after 15 days of culture. These bioprinted neural tissues expressed TUJ1 (15 ± 1.3%), the dopamine marker, tyrosine hydroxylase (TH) (8 ± 1%) and other glial markers such as glial fibrillary acidic protein (GFAP) (15 ± 4%) and oligodendrocyte progenitor marker (O4) (4 ± 1%) after 30 days. Also, quantitative polymerase chain reaction (qPCR) analysis showed these bioprinted tissues expressed TUJ1, NURR1 (gene expressed in midbrain dopaminergic neurons), LMX1B, TH, and PAX6 after 30 days. In conclusion, we have demonstrated that using a microsphere-laden bioink to bioprint hiPSC-derived NPCs can promote the differentiation of neural tissue.

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“…Several PARKs mutations have been linked to ER stress, mitochondrial dysfunction, α-synuclein (α-syn) accumulation, and other cellular defects, which are characteristics of PD 13 . A homozygous c.991 G>T (Asp331Tyr, D331Y) mutation in phospholipase A2 group 6 (PLA2G6) gene at the PARK14 locus is known to cause the common PD pathology and triggers PD-related motor symptoms [14][15][16] . Increasing evidence suggests that the PLA2G6 D331Y mutant triggers a distinct loss of DA neurons, accompanied by accumulated ER stress, mitophagy dysfunction, and reactive oxygen species (ROS) generation 17 .…”

Section: Introductionmentioning

confidence: 99%

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

Chong

Zeng

et al. 2020

Cell Death Dis

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The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson's disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.

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Reprogramming of a human induced pluripotent stem cell (iPSC) line (IBMSi012-A) from an early-onset Parkinson's disease patient harboring a homozygous p.D331Y mutation in the PLA2G6 gene

Cited by 3 publications

References 4 publications

Case Report: A case of PLA2G6 gene-related early-onset Parkinson's disease and review of literature

Case Report: A case of PLA2G6 gene-related early-onset Parkinson's disease and review of literature

3D Bioprinting Pluripotent Stem Cell Derived Neural Tissues Using a Novel Fibrin Bioink Containing Drug Releasing Microspheres

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

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