Imaging striatal dopaminergic function in <i>Phospholipase A2 Group VI</i>–related parkinsonism

Agarwal, Poojan; Hogarth, Penelope; Hayflick, Susan J.; MacLeod, Patrick; Kuriakose, Renju; McKenzie, Jessamyn; Heffernan, Nicole; Dinelle, Katherine; Stoessl, A. Jon

doi:10.1002/mds.25160

Cited by 15 publications

(27 citation statements)

References 6 publications

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“…In contrast, one of the PARK14 mutants, hiPLA2-VIA A80T , failed to rescue the neuronal phenotypes of diPLA2-VIA −/− flies (Fig. 1 B and C ) (7, 16).…”

Section: Resultsmentioning

confidence: 95%

Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mori

Hatano

Inoshita

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.

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“…In contrast, one of the PARK14 mutants, hiPLA2-VIA A80T , failed to rescue the neuronal phenotypes of diPLA2-VIA −/− flies (Fig. 1 B and C ) (7, 16).…”

Section: Resultsmentioning

confidence: 95%

Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mori

Hatano

Inoshita

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Our index patient with compound heterozygous p.D331Y and p.M358IfsX mutations had severe depression, and one of the two patients with a homozygous p.D331Y mutation also had depression and prominent psychotic symptoms. Many reports also found neuropsychiatric symptoms or behavioral changes in the initial presentations of patients with PLA2G6 mutations [3,12,13,18,23,25,27]. Early cognitive decline or psychiatric symptoms with motor symptoms, such as parkinsonism or dystonia, should prompt clinicians to include PLAN in their differential diagnoses.…”

Section: Comparison Of Patients With Different Plan-related Genotypesmentioning

confidence: 99%

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

et al. 2020

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Background: Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations. Case presentations: The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities. Conclusions: We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

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“…Parkinsonism (bradykinesia and rigidity) appeared uniformly during the disease course; however, the initial presentation varied greatly, and neuropsychological symptoms such as depression, psychosis, and cognitive decline preceded the motor problems on several occasions ( Table 1 , Table 4 ). 10 , 13 , 14 In a couple of cases, onset was in early childhood with non-specific signs of motor slowness or speech problems. 8 , 10 , 13 , 15 …”

Section: Discussionmentioning

confidence: 99%

“… 10 , 15 , 16 Other patients were either normal or imaging was not reported in detail. Iron was found in only eight patients (33%): 10 , 11 , 14 , 16 , 17 four on gradient echo (GRE) or susceptibility-weighted imaging (SWI), two on T2, and two on both T2 and GRE. Iron was deposited in the globus pallidus 10 and substantia nigra, 17 or both.…”

Section: Case Reportmentioning

confidence: 99%

“…Reduced dopamine transporter (DAT) labeling was seen in all 10 patients studied using this methodology. 8 , 12 , 14 – 18 In order to examine pre- and post-synaptic dopaminergic function, one patient received four different tracers: PET with [18]F-6-flouro- l -dopa, [11]C-dihydrotetrabenazine, and [11]C-d-thereo-methylphenidate (DAT marker) disclosed reduced presynaptic dopaminergic uptake, while [11]C-raclopride showed increased post-synaptic dopaminergic receptor labeling. Labeling with all tracers was identical to that seen in idiopathic Parkinson’s disease (IPD).…”

Section: Case Reportmentioning

confidence: 99%

See 1 more Smart Citation

PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review

Karkheiran

Shahidi

Walker

et al. 2015

Tremor and Other Hyperkinetic Movements

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Imaging striatal dopaminergic function in Phospholipase A2 Group VI–related parkinsonism

Cited by 15 publications

References 6 publications

Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review

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