PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia–parkinsonism type 14 and can be relieved by DHA treatment in animal models

Yeh, Tu-Hsueh; Liu, Han-Fang; Chiu, Ching-Chi; Cheng, Mei‐Ling; Huang, Guo-Jen; Huang, Yin-Cheng; Liu, Yu-Chien; Huang, Ying-Zu; Lu, Chin‐Song; Chen, Yi-Chieh; Chen, Hao-Yuan; Cheng, Yi-Chuan

doi:10.1016/j.expneurol.2021.113863

Cited by 6 publications

(2 citation statements)

References 38 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). Several studies have also suggested that potential enzyme activity, DNA methylation, synergistic genetics, and environmental factors may be involved in PLA2G6 gene-related neurological diseases (Guo et al, 2018), which, therefore, have diverse phenotypes.…”

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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“…In zebrafish, pla2g6 deficiency leads to death of DA neurons and axonal degeneration (Sánchez et al, 2018). Additionally, transient overexpression of human PLA2G6 loss-of-function mutants induces DA neuron degeneration and locomotion defects (Yeh et al, 2021). Therefore, Pla2g6 deficiency or dysfunction consistently causes PD phenotypes in both mouse and zebrafish models.…”

Section: Pla2g6: Phospholipase A2 Group VImentioning

confidence: 99%

Modeling familial and sporadic Parkinson's disease in small fishes

Yamanaka,

Matsui

2023

Dev Growth Differ

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The establishment of animal models for Parkinson's disease (PD) has been challenging. Nevertheless, once established, they will serve as valuable tools for elucidating the causes and pathogenesis of PD, as well as for developing new strategies for its treatment. Following the recent discovery of a series of PD causative genes in familial cases, teleost fishes, including zebrafish and medaka, have often been used to establish genetic PD models because of their ease of breeding and gene manipulation, as well as the high conservation of gene orthologs. Some of the fish lines can recapitulate PD phenotypes, which are often more pronounced than those in rodent genetic models. In addition, a new experimental teleost fish, turquoise killifish, can be used as a sporadic PD model, because it spontaneously manifests age‐dependent PD phenotypes. Several PD fish models have already made significant contributions to the discovery of novel PD pathological features, such as cytosolic leakage of mitochondrial DNA and pathogenic phosphorylation in α‐synuclein. Therefore, utilizing various PD fish models with distinct degenerative phenotypes will be an effective strategy for identifying emerging facets of PD pathogenesis and therapeutic modalities.

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Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders

Wise

Wagener

Fietzek

et al. 2022

Neurobiology of Disease

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PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia–parkinsonism type 14 and can be relieved by DHA treatment in animal models

Cited by 6 publications

References 38 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

Modeling familial and sporadic Parkinson's disease in small fishes

Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders

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