<scp>N</scp>europathology of <scp>PARK14</scp> is identical to idiopathic <scp>P</scp>arkinson's disease

Miki, Yasuo; Yoshizawa, Tadashi; Morohashi, Satoko; Seino, Yusuke; Kijima, Hiroshi; Shoji, Mikio; Mori, Akio; Yamashita, Chikara; Hatano, Taku; Wakabayashi, Keiji

doi:10.1002/mds.26952

Cited by 13 publications

(13 citation statements)

References 9 publications

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“…PLA2G6 is not only involved in the pathogenesis of PARK14-linked parkinsonism but also in idiopathic PD [ 59 , 60 ]. Mutation of PLA2G6 was found in patients affected with PARK14 or idiopathic PD [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Chiu

Yeh

et al. 2017

Oncotarget

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Mutations in the gene encoding Ca2+-independent phospholipase A2 group 6 (PLA2G6) cause the recessive familial type 14 of Parkinson’s disease (PARK14). Mitochondrial dysfunction is involved in the pathogenesis of Parkinson’s disease (PD). PLA2G6 is believed to be required for maintaining mitochondrial function. In the present study, rotenone-induced cellular model of PD was used to investigate possible molecular pathogenic mechanism of PARK14 mutant PLA2G6-induced PD. Overexpression of wild-type (WT) PLA2G6 ameliorated rotenone-induced apoptotic death of SH-SY5Y dopaminergic cells. PARK14 mutant (D331Y), (G517C), (T572I), (R632W), (N659S) or (R741Q) PLA2G6 failed to prevent rotenone-induced activation of mitochondrial apoptotic pathway and exert a neuroprotective effect. WT PLA2G6, but not PARK14 mutant PLA2G6, prevented rotenone-induced mitophagy impairment. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 was ineffective in attenuating rotenone-induced decrease in mitochondrial membrane potential and increase in the level of mitochondrial superoxide. WT PLA2G6, but not PARK14 PLA2G6 mutants, restored enzyme activity of mitochondrial complex I and cellular ATP content in rotenone-treated SH-SY5Y dopaminergic cells. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 failed to prevent rotenone-induced mitochondrial lipid peroxidation and cytochrome c release. These results suggest that PARK14 PLA2G6 mutants lose their ability to maintain mitochondrial function and are defective inpreventing mitochondrial dysfunction, ROS production and activation of mitochondrial apoptotic pathway in rotenone-induced cellular model of PD.

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Section: Discussionmentioning

confidence: 99%

PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Chiu

Yeh

et al. 2017

Oncotarget

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“…The typical phenotype consists of infantile neuroaxonal dystrophy characterized by progressive motor and mental retardation, marked truncal hypotonia, cerebellar ataxia, pyramidal signs, and optic atrophy . Later onset (as late as in the 40s) may present with milder phenotype, for example, with complicated levodopa‐responsive dystonia‐parkinsonism . Brain iron accumulation is often present.…”

Section: Autosomal Recessive Causes Of Pdmentioning

confidence: 99%

“…A summary of brain pathology is presented in Table . A total of 9 PLA2G6 mutation carriers have been examined pathologically, including 3 with a diagnosis of PD (with death 5, 23, and 31 years after onset) . Overall, LBs are usually present and may be severe .…”

Section: Autosomal Recessive Causes Of Pdmentioning

confidence: 99%

“…67 Later onset (as late as in the 40s) may present with milder phenotype, for example, with complicated levodopa-responsive dystonia-parkinsonism. [68][69][70] Brain iron accumulation is often present. A summary of brain pathology is presented in Table 6.…”

Section: Pla2g6 (Park14)mentioning

confidence: 99%

“…A total of 9 PLA2G6 mutation carriers have been examined pathologically, including 3 with a diagnosis of PD (with death 5, 23, and 31 years after onset). 68,70,71 Overall, LBs are usually present and may be severe. 72 In these cases, there were severe loss of neurons, replacement gliosis, and rare LBs present in the SN and LC.…”

Section: Pla2g6 (Park14)mentioning

confidence: 99%

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Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

2017

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Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson’s disease (PD). However mounting data from genetic-PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. Here we review the literature of genetic-PD autopsies from cases with molecularly-confirmed PD or parkinsonism and summarize main findings on SNCA (n=25), Parkin (n=20, 17 bi-allelic and 3 heterozygotes), PINK1 (n=5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n=1), LRRK2 (n=55), GBA (n=10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n= 8 patients, two with PD), MPAN (n=2), FBXO7, RAB39B and ATXN2 (SCA2), as well as on 22q deletion syndrome (n=3). Findings from autopsies of heterozygous mutation carriers of genes which are traditionally considered recessively-inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (e.g., MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (e.g., LRRK2-PD or Parkin-PD). Therefore, we may conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number of reported genetic-PD autopsies remains small and there are limited genotype-clinical-pathological-phenotype studies. Therefore, larger series of autopsies from genetic-PD patients are required.

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Genetic Movement Disorders Commonly Seen in Asians

Jagota

Lim

Pal

et al. 2023

Movement Disord Clin Pract

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The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.

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Neuropathology of PARK14 is identical to idiopathic Parkinson's disease

Cited by 13 publications

References 9 publications

PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Genetic Movement Disorders Commonly Seen in Asians

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