DOCSLIB.ORG

Intrafamilial Variability and Clinical Heterogeneity in a Family with PLA2G6-Associated Neurodegeneration

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intrafamilial Variability and Clinical Heterogeneity in a Family with PLA2G6-Associated Neurodegeneration Precision and Future Medicine 2019;3(3):135-138 CASE https://doi.org/10.23838/pfm.2019.00086 REPORT pISSN: 2508-7940 · eISSN: 2508-7959 Intrafamilial variability and clinical heterogeneity in a family with PLA2G6-associated neurodegeneration 1 2,3 2,3 Jong Kyu Park , Jinyoung Youn , Jin Whan Cho 1 DepartmentofNeurology,SoonchunhyangUniversityCheonanHospital,SoonchunhyangUniversityCollegeofMedicine, Cheonan,Korea 2 DepartmentofNeurology,SamsungMedicalCenter,SungkyunkwanUniversitySchoolofMedicine,Seoul,Korea 3 NeuroscienceCenter,SamsungMedicalCenter,Seoul,Korea Received: August 8, 2019 Revised: August 21, 2019 Accepted: August 23, 2019 ABSTRACT PhospholipaseA2groupVI(PLA2G6)-associatedneurodegeneration(PLAN)isanauto- Corresponding author: Jin Whan Cho somalrecessiveneurodegenerativediseasewithawideclinicalspectrum;however,the Department of Neurology, genotype-phenotypecorrelationisunknown.Here,wereportdifferentphenotypesin Samsung Medical Center, onefamilywiththesamegenotype.A28-year-oldmalepresentedwithslowlyprogres- Sungkyunkwan University sivegaitdisturbancewithspasticity.Onsetoccurredat11years.Interestingly,his School of Medicine, 81 Irwon- youngerbrother,a24-year-oldmale,presentedwithprogressiveParkinsonism,which ro, Gangnam-gu, Seoul 06351, beganat22years.Heshowedexcellentresponsetolevodopabutdevelopedafluctuat- Korea ingmedicationresponseandlevodopa-induceddyskinesia1yearafterstartinglevodo- Tel: +82-2-3410-3599 pamedication.Healsodemonstratedhyperreflexia,butnospasticity.Dopaminetrans- E-mail: porterimagingshowedreduceduptakeinthebilateralputamen.Inwhole-exome [email protected] sequencingandSangersequencing,ahomozygouspathogenicvariant(p.R747W)in thePLA2G6genewasdetectedinbothcases.Despitedifferentclinicalfeatures,both subjectshadhyperreflexiaduringtheexaminationandclavalhypertrophywasshown onthebrainmagneticresonanceimaging. Keywords: PLA2G6;Parkinsondisease;Geneticanalysis INTRODUCTION PhospholipaseA2groupVI(PLA2G6)-associatedneurodegeneration(PLAN)isanautosomal recessiveneurodegenerativediseasewithmultiplephenotypes,includinginfantileneuroaxo- naldystrophy,neurodegenerationwithbrainironaccumulation,anddystonia-Parkinsonism [1,2].TheclinicalspectrumofPLANhasbeenproposedtoincludevariousphenotypesassoci- This is an Open Access article atedwithPLA2G6mutations.AlthoughvariousphenotypesareknowninpatientswithPLAN, distributed under the terms of the genotype-phenotypecorrelationhasyettobeclearlyelucidated.Further,therearenoreports Creative Commons Attribution demonstratingvariousphenotypeseveninonefamilywiththesamegenotype.Here,wede- Non-Commercial License (http:// creativecommons.org/licenses/ scribeafamilywiththesamegenotypeofPLAN,butwithphenotypicvariability. by-nc/4.0/). Copyright © 2019 Sungkyunkwan University School of Medicine 135 IntrafamilialvariabilityinPLA2G6mutation CASE REPORTS ousparentsofArabianancestry.Hehadnohistoryofpreterm deliveryorperinatalinjury,andhisdevelopmentalmile- Subject 1 stoneswerenormal.Therewasnofamilyhistoryofmove- A28-year-oldmalewithprogressivespasticgaitdisturbance mentdisorders,exceptinhisyoungerbrother(Subject2). thatbeganattheageof11presentedatSamsungMedical ThefamilialpedigreeisillustratedinFig.1.Hewasnormalin Center,Seoul,Korea.Hewasborntohealthyconsanguine- cognitiveandlanguageskillsandfinishedhismaster’sde- greeincollege.Theonlyaccompanyingsymptomwasuri- naryurgencyandincontinence. Whenhecametoourclinic,spasticitywaspresentinthe hipadductormuscles,aswellasinthekneeandanklejoints. Sensorydisturbanceoflowerlimbswasabsent.Briskreflex- eswerepresentonbothlimbs,andpathologicreflexes,such asHoffmansign,ankleclonusandBabinskisign,werealso present.Grade4mildmuscleweaknesswaspresentwith bothankledorsiflexions.Hedemonstratedspasticgaitwith dystonicanklemovementsinterferingspeedofgait,butno rigidityorbradykinesia.Anerveconductionstudyonlower limbswasnormal.Therewasnoironaccumulation,butcla- valhypertrophywasshownonthebrainmagneticresonance imaging(MRI)(Fig.2A).Thecervicalthroughthoracicspinal Fig. 1. Pedigree of the index subjects: black symbols indicate MRIwasnormal. affected individuals and arrows indicate subjects. A B C Fig. 2. (A) T2 fluid attenuated inversion recovery (FLAIR) midsagittal section image of subject 1 shows claval hypertrophy (white arrow). (B) T2 FLAIR midsagittal section image of subject 2 shows claval hypertrophy (white arrow) and a vertical corpus callosum (black arrow). (C) Dopamine transporter image of subject 2 demonstrated significantly reduced uptake in the bilateral putamen. 136 http://pfmjournal.org JongKyuPark,etal. Fig. 3. Sequencing analysis of index subjects showing homozygous variants in phospholipase A2 group VI (PLA2G6). Analysis of parental samples demonstrated that the PLA2G6 variants were heterozygous, which is consistent with autosomal recessive inheritance. Wholeexomesequencingforsubject1revealedahomozy- andthesamehomozygouspathogenicvariant(p.R747W) gousc.2239C> T(p.R747W)pathogenicvariantinthePLA2G6 wasdetected(Fig.3).HisParkinsonismimproveddramati- gene.Sangersequencingshowedthatbothoftheparents callywithlevodopamedication,buthedevelopedwear- wereheterozygousforthisvariant(Fig.3).Hisgaitdistur- ing-offphenomenonandlevodopa-induceddyskinesiawith- bancedidnotrespondwithlevodopatreatmentbutpartially in1yearfromthelevodopastartdate. improvedwithbaclofen(30mg/day)andbotulinumtoxin typeAinjectiononthetibialisposteriormuscle(50units, DISCUSSION each). Here,wedescribedtwodifferentphenotypesofthesame Subject 2 genotypeofPLANinonefamily.Onephenotypewaslevodo- Theyoungerbrotherofsubject1,a24-year-oldmale,pre- pa-responsiveParkinsonismandtheotherwasspasticpara- sentedatourclinicwithslowlyprogressiveParkinsonism plegia.Bothsharedhyperreflexiaonlowerlimbsandpyrami- thatbeganattheageof22.Likesubject1,hehadnohistory daltractsyndrome,buttotallydifferentmainphenotypic ofpretermdeliveryorperinatalinjury,andthedevelopmen- presentationsinthesamegenotypearerarelyreported.In- talmilestoneswerenormal.Urinaryurgencywascombined, terestingly,PLANcoversvariousphenotypesofPLA2G6mu- whilegeneralcognitionwasnormal. tation,andvariousphenotypesofPLANaredescribedac- Ontheneurologicexam,bradykinesiaandrigiditywere cordingtotheageofonset(e.g.,infantileneuroaxonaldys- presentinbothlimbs,butmoreprominentlyontheleftside. trophyoccursinchildhoodanddystonia-Parkinsonismoc- Additionally,resttremorwasseeninbotharms.Deepten- cursinearlyadulthood).However,eventhoughvariousphe- donreflexeswerebriskandtheBabinskisignwaspresentin notypesofPLANhavebeenreported,therearecurrentlyin- bothlowerlimbs.F-18fluorinated-N-3-fluoropropyl-2-b-car- sufficientstudiesonphenotype-genotypecorrelation.Fur- boxymethoxy-3-b-(4-iodophenyl)nortropanepositronemis- ther,ourpatientsweresimilarinagebutpresentedwith siontomography(FP-CITPET)demonstratedsignificantlyre- completelydifferentphenotypesinasinglefamilywiththe duceduptakeinthebilateralputamen(Fig.2C).Additionally, samegenotype,unlikevariousphenotypesinPLAN.Tothe corpuscallosumchangesandclavalhypertrophywereseen bestofourknowledge,thisisthefirstreportofintrafamilial onthebrainMRI(Fig.2B). variabilityinmonogenicPLAN.Themechanismsresponsible WeperformedSangersequencingofthePLA2G6gene, fordeterminationofphenotypesarenotyetknown. https://doi.org/10.23838/pfm.2019.00086 137 IntrafamilialvariabilityinPLA2G6mutation Thefirstphenotypeofoursubjectswaslevodopa-respon- CONFLICTS OF INTEREST siveParkinsonism.Parkinsonismisacommonlyreported symptominPLANpatients,andthesamegenotype(p. Nopotentialconflictofinterestrelevanttothisarticlewasre- R747W)hasbeenpreviouslyreportedinapatientwith ported. levodopa-responsiveParkinsonism[3,4].Inaccordancewith previouslyreportedPLANcaseswithParkinsonism,ourcase ORCID alsoshowednormalbirth,achievednormalmilestones,and symptomsbeganinadulthood.Allcasesprogressedrapidly JongKyuPark https://orcid.org/0000-0002-9261-790X aftertheonsetandshowedadramaticresponsetolevodopa JinyoungYoun https://orcid.org/0000-0003-3350-5032 therapy,butanimpulsecontroldisorderorearlydyskinesia JinWhanCho https://orcid.org/0000-0002-9145-6729 appeared.Additionally,ourcasealsorevealedpresynaptic dopaminergiclossbyFP-CITPETimagingstudy. REFERENCES Intermsofspasticparaplegia,60hereditaryspasticpara- plegia(HSP)-relatedgeneshavebeenreported,buttheun- 1. GuoYP,TangBS,GuoJF.PLA2G6-associatedneurode- derlyingcausesofHSPstillremainunidentified[5].Recently, generation(PLAN):reviewofclinicalphenotypesand PLANwithphenotypeofcomplicatedHSPwasreported[6,7], genotypes.FrontNeurol2018;9:1100. butpureformspasticparaplegiawasnotreported.With 2. LeeJH,ParkJ,RyuHS,ParkH,KimYE,HongJY,etal.Clin- wholeexomesequencing,weexcludedassociatedgenesfor icalheterogeneityofatypicalpantothenatekinase-asso- HSPinsubject1;thus,wesuggestpureformspasticparaple- ciatedneurodegenerationinKoreans.JMovDisord2016; giaisanewphenotypeofPLANbasedonourcase. 9:20-7. Despitedifferentmainphenotypesofourpatients,both 3. Paisan-RuizC,LiA,SchneiderSA,HoltonJL,JohnsonR, subjectsalsodemonstratedcommonclinicalfeatures.First, KiddD,etal.WidespreadLewybodyandtauaccumulation pyramidaltractsyndromewasseeninbothsubjects.Addi- inchildhoodandadultonsetdystonia-parkinsonismcases tionally,bothcaseshadclavalhypertrophy(Fig.2A,B).In withPLA2G6mutations.NeurobiolAging2012;33:814-23. termsofbrainimaging,abnormalironaccumulationiscon- 4. GiriA,GuvenG,HanagasiH,HauserAK,Erginul-Unaltuna sideredasacharacteristicsignofneurodegenerationwith N,BilgicB,etal.PLA2G6mutationsrelatedtodistinct brainironaccumulation,butironaccumulationisnolonger phenotypes:anewcasewithearly-onsetparkinsonism. apathognomonicfindinginPLA2G6mutations.Similarly,
Load more

Recommended publications
  • File Download
    ADP Ribosylation Factors 1 and 4 and Group VIA Phospholipase A(2) Regulate Morphology and Intraorganellar Traffic in the Endoplasmic Reticulum-Golgi Intermediate Compartment Houchaima Ben-Tekaya, University of Basel Richard Kahn, Emory University Hans-Peter Hauri, University of Basel Journal Title: Molecular Biology of the Cell Volume: Volume 21, Number 23 Publisher: American Society for Cell Biology | 2010-12-01, Pages 4130-4140 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1091/mbc.E10-01-0022 Permanent URL: https://pid.emory.edu/ark:/25593/ttrdd Final published version: http://dx.doi.org/10.1091/mbc.E10-01-0022 Copyright information: © 2010 H. Ben-Tekaya et al. This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/). Accessed September 28, 2021 7:22 PM EDT Molecular Biology of the Cell Vol. 21, 4130–4140, December 1, 2010 ADP Ribosylation Factors 1 and 4 and Group VIA Phospholipase A2 Regulate Morphology and Intraorganellar Traffic in the Endoplasmic Reticulum–Golgi Intermediate Compartment Houchaima Ben-Tekaya,* Richard A. Kahn,† and Hans-Peter Hauri* *Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and †Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322 Submitted January 8, 2010; Revised September 15, 2010; Accepted September 22, 2010 Monitoring Editor: Adam Linstedt Organelle morphology of the endomembrane system is critical for optimal organelle function. ADP ribosylation factors (Arfs), a family of small GTPases, are required for maintaining the structure of the Golgi and endosomes.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • Anti-Phospholipase A2 (Ipla2) (C-Terminal Region) Produced in Rabbit, Affinity Isolated Antibody
    Anti-Phospholipase A2 (iPLA2) (C-terminal region) produced in rabbit, affinity isolated antibody Product Number SAB4200130 Product Description iPLA2 group VIA comprises at least 5 alternatively Anti-Phospholipase A2 (iPLA2) (C-terminal region) is spliced isoforms. Isoforms LH-iPLA2 (90 kDa), and produced in rabbit using as the immunogen a synthetic SH-iPLA2 (85 kDa) iPLA2 have been implicated in peptide corresponding to a sequence at the C-terminal phospholipid remodeling, nitric oxide-induced or of human iPLA2 (GeneID 8398), conjugated to KLH. vasopressin-induced arachidonic acid release, and in The corresponding sequence is highly conserved in leukotriene and prostaglandin production. Mutations in mouse iPLA2 (83% identity) and in rat iPLA2 (72% the PLA2G6 gene are the cause of two childhood identity). The antibody is affinity-purified using the neurologic disorders, neurodegeneration with brain iron immunizing peptide immobilized on agarose. accumulation (NBIA) and infantile neuroaxonal 4,5 dystrophy 1 (INAD1). Recent evidence suggests that Anti-Phospholipase A2 (iPLA2) (C-terminal region), both cPLA2 and iPLA2 may play a central role in specifically recognizes human and rat iPLA2. The memory deficits at early stages of AD and in the AD antibody can be used in several immunochemical neurodegenerative process.6 techniques including immunoblotting (85 kDa human iPLA2, and 95 kDa rat iPLA2). Detection of the iPLA2 Reagent bands by immunoblotting is specifically inhibited by the Supplied as a solution in 0.01 M phosphate buffered iPLA2 immunizing peptide. saline, pH 7.4, containing 15 mM sodium azide. 2+ Ca -independent phospholipase A2 (iPLA2, also known Antibody concentration: 1.5 mg/mL as PLA2G6, INAD1, PARK14, PNPLA9) is a member of the PLA2 superfamily that catalyzes the cleavage of Precautions and Disclaimer fatty acids from the sn-2 position of phospholipids.1,2 For R&D use only.
    [Show full text]
  • Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: a Canonical Pathway
    Lipid related genes altered in NASH connect inflammation in liver pathogenesis progression to HCC: a canonical pathway Christophe Desterke1, Franck Chiappini2* 1 Inserm, U935, Villejuif, F-94800, France 2 Cell Growth and Tissue Repair (CRRET) Laboratory, Université Paris-Est Créteil (UPEC), EA 4397 / ERL CNRS 9215, F-94010, Créteil, France. Corresponding author: *Franck Chiappini. Laboratoire du CRRET (Croissance, Réparation et Régénération Tissulaires), Université Paris-Est Créteil, 61 avenue du Général de Gaulle F- 94010, Créteil Cedex, Val de Marne, France. Email address: [email protected]; Tel: +33(0)145177080; Fax: +33(0)145171816 Supplementary Information Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Supplementary Datasets Table S2: Expression fold change of lipid related genes found differentially expressed between NASH and healthy obese liver samples. Supplementary Datasets Table S3: Liver as principal filter for prioritization of lipid related genes found differentially expressed in NASH. Supplementary Datasets Table S4: Gene prioritization secondary filters (immunological, inflammation, liver pathogenesis progression) table found with lipid related genes differentially expressed in NASH. Supplementary Datasets Table S5: Identification of protein partners of YWHAZ gene using InnateDB database. Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Ranking of "lipidic" textmining Gene symbol
    [Show full text]
  • Catalytic Function of PLA2G6 Is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but Not Dystonia-Parkinsonism Laura A
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2010 Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism Laura A. Engel Washington University School of Medicine in St. Louis Zheng Jing Washington University School of Medicine in St. Louis Daniel E. O’Brien Washington University School of Medicine in St. Louis Mengyang Sun Washington University School of Medicine in St. Louis Paul T. Kotzbauer Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Part of the Medicine and Health Sciences Commons Recommended Citation Engel, Laura A.; Jing, Zheng; O’Brien, Daniel E.; Sun, Mengyang; and Kotzbauer, Paul T., ,"Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism." PLoS One.,. e12897. (2010). https://digitalcommons.wustl.edu/open_access_pubs/674 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Catalytic Function of PLA2G6 Is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but Not Dystonia-Parkinsonism Laura A. Engel, Zheng Jing, Daniel E. O’Brien, Mengyang Sun, Paul T. Kotzbauer* Departments of Neurology and Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America Abstract Background: Mutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia- parkinsonism.
    [Show full text]
  • Genes Implicated in Familial Parkinson's Disease Provide a Dual
    International Journal of Molecular Sciences Review Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage Rafael Franco 1,2,† , Rafael Rivas-Santisteban 1,2,† , Gemma Navarro 2,3,† , Annalisa Pinna 4,*,† and Irene Reyes-Resina 1,†,‡ 1 Department Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain; [email protected] (R.F.); [email protected] (R.R.-S.); [email protected] (I.R.-R.) 2 Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, 28031 Madrid, Spain; [email protected] 3 Department Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain 4 National Research Council of Italy (CNR), Neuroscience Institute–Cagliari, Cittadella Universitaria, Blocco A, SP 8, Km 0.700, 09042 Monserrato (CA), Italy * Correspondence: [email protected] † These authors contributed equally to this work. ‡ Current address: RG Neuroplasticity, Leibniz Institute for Neurobiology, Brenneckestr 6, 39118 Magdeburg, Germany. Abstract: The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) Citation: Franco, R.; Rivas- is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein Santisteban, R.; Navarro, G.; Pinna, (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a A.; Reyes-Resina, I. Genes Implicated narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, in Familial Parkinson’s Disease VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in Provide a Dual Picture of Nigral familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of Dopaminergic Neurodegeneration dopaminergic denervation in many types of PD.
    [Show full text]
  • Parkinson's Disease-Related Genes and Lipid Alteration
    International Journal of Molecular Sciences Review Parkinson’s Disease-Related Genes and Lipid Alteration Milena Fais 1 , Antonio Dore 2, Manuela Galioto 1, Grazia Galleri 3 , Claudia Crosio 1 and Ciro Iaccarino 1,* 1 Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; [email protected] (M.F.); [email protected] (M.G.); [email protected] (C.C.) 2 Istituto di Scienza delle Produzioni Alimentari, CNR, 07040 Sassari, Italy; [email protected] 3 Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-079-228610 Abstract: Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein Citation: Fais, M.; Dore, A.; Galioto, accumulation—and finally neuronal death.
    [Show full text]
  • Complicated Spastic Paraplegia in Patients with AP5Z1 Mutations (SPG48)
    Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48) Jennifer Hirst, PhD* ABSTRACT * Marianna Madeo, PhD Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 z subunit have been * Katrien Smets, MD described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we James R. Edgar, PhD sought to define genotype–phenotype correlations in patients with homozygous or compound Ludger Schols, MD, heterozygous sequence variants predicted to be deleterious. Dr med Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic Jun Li, MD, PhD mutations in AP5Z1. Anna Yarrow, BA z Tine Deconinck, MSci Results: In 4 of the 6 patients, there was complete loss of AP-5 protein. Clinical features encom- Jonathan Baets, MD, passed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dysto- PhD nia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic Elisabeth Van Aken, MD, acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated PhD lamellar storage material consistent with abnormal storage of lysosomal material. Jan De Bleecker, MD, Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders PhD and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and Manuel B. Datiles III, lysosomal storage disorders. Neurol Genet 2016;2:e98; doi: 10.1212/NXG.0000000000000098 MD Ricardo H. Roda, MD, GLOSSARY PhD HSP 5 hereditary spastic paraplegia; NCS 5 nerve conduction study; PAS 5 periodic acid-Schiff; PSP 5 progressive supra- 5 Joachim Liepert, MD nuclear palsy; SCA spinocerebellar ataxia.
    [Show full text]
  • Genetic Analysis of ATP13A2, PLA2G6 and FBXO7 in a Cohort Of
    www.nature.com/scientificreports OPEN Genetic analysis of ATP13A2, PLA2G6 and FBXO7 in a cohort of Chinese patients with early-onset Received: 13 March 2018 Accepted: 24 August 2018 Parkinson’s disease Published: xx xx xxxx Ting Shen1,2, Jiali Pu1, Hsin-Yi Lai1,2, Lingjia Xu1, Xiaoli Si1, Yaping Yan1, Yasi Jiang2 & Baorong Zhang1 Several genes have already been certifed as causative genes in patients with autosomal recessive early-onset Parkinson’s syndrome with pyramidal tract signs, including ATP13A2, PLA2G6 and FBXO7. Variants in these three genes may also play roles in early-onset Parkinson’s disease (EOPD). In order to investigate the contribution of genetic variants in these three genes to Chinese sporadic EOPD patients, we screened 101 Chinese sporadic EOPD patients and 83 age- and sex-matched healthy controls using direct sequencing. Interpretation of those detected variants was performed based on the guidelines developed by the American College of Medical Genetics and Genomics (ACMG). Two missense variants, p.G360E and p.T733M, with “uncertain signifcance” classifcation were identifed in the ATP13A2 gene and fve synonymous variants were signifcantly over-represented in EOPD patients. Two missense variants, p.R53C and p.T319M, were absent in both our control group and online databases, classifed as “likely pathogenic” in the PLA2G6 gene. Only benign variants were identifed in the FBXO7 gene. These results indicate that rare variants of PLA2G6 may contribute to PD susceptibility in Chinese population, the ATP13A2 might be associated with higher risk for sporadic EOPD, while the FBXO7 gene doesn’t seem to be a risk factor to develop sporadic PD in Chinese population.
    [Show full text]
  • Putative Second Hit Rare Genetic Variants in Families with Seemingly
    www.nature.com/npjgenmed ARTICLE OPEN Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease ✉ Muhammad Aslam 1 , Nirosiya Kandasamy1, Anwar Ullah 1,2,3, Nagarajan Paramasivam4, Mehmet Ali Öztürk5,6, Saima Naureen1,7, Abida Arshad7, Mazhar Badshah8, Kafaitullah Khan9, Muhammad Wajid10, Rashda Abbasi2, Muhammad Ilyas11, Roland Eils 12,13, ✉ Matthias Schlesner 14, Rebecca C. Wade 5,15, Nafees Ahmad2 and Jakob von Engelhardt1 Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild- type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells.
    [Show full text]
  • Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS
    brain sciences Article Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS Oge Gozutok 1, Benjamin Ryan Helmold 1 and P. Hande Ozdinler 1,2,3,4,* 1 Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA; [email protected] (O.G.); [email protected] (B.R.H.) 2 Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60611, USA 3 Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 4 Feinberg School of Medicine, Les Turner ALS Center at Northwestern University, Chicago, IL 60611, USA * Correspondence: [email protected]; Tel.: +1-(312)-503-2774 Abstract: Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein- protein interactions, we hypothesized that the mutations detected in patients and the alterations in Citation: Gozutok, O.; Helmold, B.R.; protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. Ozdinler, P.H. Mutations and Protein In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction Interaction Landscape Reveal Key Cellular Events Perturbed in Upper partners of proteins and developed the protein-protein interaction landscape with respect to HSP Motor Neurons with HSP and PLS.
    [Show full text]
  • Curriculum Vitae
    CURRICULUM VITAE NAME: Vladimir A. TYURIN BUSINESS ADDRESS: Department of Environmental and Occupational Health, University of Pittsburgh, 130 DeSoto st., Public Health, Room # 4117, Pittsburgh, PA 15261 Phone:412-624-8596 Fax:412-624-9361 E-mail:[email protected] EDUCATION AND TRAINING Undergraduate 1968-1973 Far East State University, M.S., 1973 BiophysiCs Vladivostok, Russia Graduate 1976-1980 MosCow State Ph.D., 1980 BiophysiCs University, MosCow, Russia Post-Graduate 1997-2000 Department of Fellowship from the Prof. V.E. Kagan Environmental and NIH, NCI “OnCology Prof. J. LaZo OcCupational Health, ResearCh FaCulty Graduate SChool of Development PubliC Health, University Program”, The of Pittsburgh, Pittsburgh, program prepares PA, U.S.A. participants for careers as independent investigators and for leadership positions in canCer research. 1999-2000 Department of Fellowship from the Prof. V.E. Kagan Environmental and Magee-Womens OcCupational Health, ResearCh Institute, Graduate SChool of University of PubliC Health, University Pittsburgh. of Pittsburgh, Pittsburgh, PA, U.S.A. APPOINTMENTS AND POSITIONS Academic 1973-1976 ResearCh Assistant Laboratory BioChemistry of Vision ResearCh, (BioChemistry, Biophysics) Institute of Marine Biology Far East SCientific Center of Russian Academy of SCienCe, Vladivostok, Russia. 1976-1980 ResearCh sCientist in Laboratory BioChemistry of Vision ResearCh, BioChemistry, BiophysiCs Institute of Marine Biology Far East SCientific Center of Russian Academy of SCienCe, Vladivostok, Russia. 1981-1984 ResearCh sCientist in Laboratory of NeuroChemistry, Institute of BioChemistry, BiophysiCs Evolutionary Physiology and Biochemistry, Russian Academy of SCienCe, St.-Petersburg, Russia. 1984-1995 ResearCh AssoCiate Laboratory of Comparative BioChemistry of Nervous System, Institute of Evolutionary Physiology and Biochemistry, Russian Academy of SCienCe, St.-Petersburg, Russia.
    [Show full text]