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Review ArticleReview Article

Parkinson Disease: Translating Insights from Molecular Mechanisms to Neuroprotection

Sheila K. Pirooznia, Liana S. Rosenthal, Valina L. Dawson and Ted M. Dawson
Eric Barker, ASSOCIATE EDITOR
Pharmacological Reviews October 2021, 73 (4) 1204-1268; DOI: https://doi.org/10.1124/pharmrev.120.000189
Sheila K. Pirooznia
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (S.K.P., V.L.D., T.M.D.), Departments of Neurology (S.K.P., L.S.R., V.L.D., T.M.D.), Departments of Physiology (V.L.D.), Solomon H. Snyder Department of Neuroscience (V.L.D., T.M.D.), Department of Pharmacology and Molecular Sciences (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.); and Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.)
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Liana S. Rosenthal
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (S.K.P., V.L.D., T.M.D.), Departments of Neurology (S.K.P., L.S.R., V.L.D., T.M.D.), Departments of Physiology (V.L.D.), Solomon H. Snyder Department of Neuroscience (V.L.D., T.M.D.), Department of Pharmacology and Molecular Sciences (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.); and Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.)
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Valina L. Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (S.K.P., V.L.D., T.M.D.), Departments of Neurology (S.K.P., L.S.R., V.L.D., T.M.D.), Departments of Physiology (V.L.D.), Solomon H. Snyder Department of Neuroscience (V.L.D., T.M.D.), Department of Pharmacology and Molecular Sciences (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.); and Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.)
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Ted M. Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (S.K.P., V.L.D., T.M.D.), Departments of Neurology (S.K.P., L.S.R., V.L.D., T.M.D.), Departments of Physiology (V.L.D.), Solomon H. Snyder Department of Neuroscience (V.L.D., T.M.D.), Department of Pharmacology and Molecular Sciences (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.); and Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana (S.K.P., V.L.D., T.M.D.)
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Eric Barker
Roles: ASSOCIATE EDITOR
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    Fig. 1

    Causal relationship between PD-linked genes and multifactorial dopaminergic neurotoxicity. Pathogenic mutations in multiple PD genes disrupt basic cellular functions in dopaminergic neurons. Aggregation of α-synuclein is increased under conditions of oxidative or nitrosative stress that activate c-Abl, leading to accumulation of phosphotyrosine 39 (P-Y39) in brain tissues and Lewy bodies. Activation of c-Abl also impairs catalytic activity of parkin, inhibiting its proteosomal and mitochondrial functions. Abnormal associations of α-synuclein with the mitochondria cause mitochondrial membrane permeabilization and dysfunction. Aggregated α-synuclein impairs various basic cellular functions along the nigrostriatal pathway, culminating in dopaminergic neurotoxicity. A pathogenic link between defective protein sorting and PD is exemplified by pathogenic mutations in α-synuclein, LRRK2, VPS35, and DNAJC6 [DnaJ Heat Shock Protein Family (Hsp40) Member C6]. Mutations in α-synuclein, LRRK2, GBA, or ATP13A2 also impair the lysosomal-autophagy pathway and interfere with lysosomal degradation of several substrates, most notable of which is α-synuclein, setting forth feed-forward cycles of lysosomal toxicity and LB pathology. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

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    Fig. 2

    PINK1 and parkin at the foci of mitochondrial quality control. PINK1 and parkin are central to the regulation of multiple sequential and parallel pathways that promote mitochondrial removal and regeneration. Activation of PINK1 and parkin in response to widespread mitochondrial damage leads to clearance of damaged organelles via mitophagy. Turnover of damaged mitochondrial components is facilitated by PINK/parkin-mediated generation of mitochondria-derived vesicles (MDV) that are transported to lysosomes for degradation. To replenish functional mitochondria, PINK1 and parkin target the pathogenic substrate PARIS for sequential phosphorylation and proteosomal degradation, relieving PARIS repression of PGC-1α to stimulate mitochondrial biogenesis. Besides PINK1, antioxidant properties of DJ-1 protect against oxidative stress. IRS, insulin response sequence; Mfn, Mitofusin; NRF1, Nuclear Respiratory Factor 1; Ub, ubiquitin; VDAC, voltage-dependent anion channel. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

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    Fig. 3

    Potential interventions to curb α-synuclein spreading. Multiple routes are known to facilitate cell-to-cell spread of α-synuclein fibrils, including direct diffusion, endocytosis, or specific receptor-mediated uptake. Endocytosed fibrils are trafficked to lysosomes, and acidic environments in lysosomes favor aggregate formation, essentially serving as nucleation sites. Eventual rupture of these lysosomes plant α-synuclein aggregates in the cytosol forming intracellular pathologic inclusions that continue to grow by recruiting and sequestering other soluble cytosolic proteins. Blocking fibril transmission and enhancing lysosomal substrate degradation could curb interneuronal propagation and thus hold therapeutic potential. Targeting α-synuclein receptors such as LAG3 or APLP1 using specific antibodies could be neuroprotective. Eliminating pathogenic interactions between α-synuclein and microglia in the extracellular milieu could dampen neurotoxic inflammatory responses in the brain. If progressed stages of the disease are associated with increased exosomal release, pathogenic α-synuclein containing exosomes in body fluids could be accessed for quantification as a potential biomarker of disease progression. Strategies aimed at promoting enhanced clearance of extracellular α-synuclein using immunotherapy could be beneficial. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

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    Fig. 4

    PAR-mediated dopaminergic cell death pathways. Hyperactivation of PARP1 and cellular accumulation of PAR lead to neuronal cell death via parthanatos. PARP1 can be activated by the accumulation of the parkin substrate AIMP2 under conditions of parkin inactivation and pathologic α-syn (α-syn PFF)–induced oxidative and/or nitrosative stress. This leads to translocation of excess PAR to the cytosol, which promotes the mitochondrial release of AIF and its interaction with MIF. Nuclear translocation of MIF causes genomic stress, which in turn may further activate PARP1 and the ensuing parthanatos-mediated cell death. In a feed-forward loop, PAR interacts with α-syn, increasing its aggregation potential and interneuronal transmission, resulting in further cellular toxicity. This figure was drawn by Noelle Burgess. Copyright JHU/ICE. Permission granted by JHU/ICE.

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    Fig. 5

    Neuroinflammatory mechanisms underlying dopaminergic toxicity. Toxic forms of α-synuclein released from nigrostriatal dopamine and other susceptible neurons activate microglia that can be detrimental to dopaminergic neurons through various pathways. 1) Activated microglia can phagocytose and degrade neurons. 2) Cytokine release from activated microglia promotes microglial clustering around dopamine neurons, triggering self-perpetuating cycles of chronic neuroinflammation and eventually resulting in cell death. 3) Activation of the NLRP3 inflammasome by α-synuclein, mitochondrial damage, and ROS also leads to neurotoxic inflammatory responses. 4) Activated microglia can also elicit CD8+ cytotoxic T-cell response by inducing dopaminergic expression of MHC-I molecules that aid in antigen presentation. 5) Inflammatory activation of microglia can subsequently activate astrocytes and their upregulation of NF-κB responsive proinflammatory genes that lead to NO and ROS production. 6) Activated microglia also induce a subtype of reactive neurotoxic astrocytes, termed A1 astrocytes, by secreting IL-1α, TNF-α, and C1q. Transfer of α-synuclein from diseased neurons to surrounding astrocytes can also lead to induction of proinflammatory gene expression. Signaling pathways within reactive microglia and astrocytes thus hold therapeutic potential. These include blocking the formation of activated A1 astrocytes via microglia formation of IL-1 α, TNF- α, and C1q. Targeting the orphan nuclear receptor Nurr1 (NR4A2) to promote anti-inflammatory effects in microglia and astrocytes may be beneficial. Blockage of IL-1β, soluble TNF, and other cytokines or iNOS production that stem from microglial activation also holds promise as therapy. Regulation of NLRP3 inflammasome activity could counter neuroinflammatory responses. TCR, T-cell receptor. This figure was drawn by I-Hsun Wu. Copyright JHU/ICE. Permission granted by JHU/ICE.

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    Fig. 6

    Adaptive immunity in Parkinson disease. Leakage of aberrant proteins such as nitrated α-syn (N-Syn) into the lymphatic system after nigrostriatal and other susceptible neuronal injury triggers T-cell response by producing antigenic epitopes. T-cell recognition of α-syn peptides presented by MHC class II–expressing antigen-presenting cells leads to proliferation of effector T cells, in particular, IL-5–secreting CD4+ T cells and IFNγ-secreting CD8+ cytotoxic T cells triggering neurotoxic immune responses. Cytokines released from microglia activated by α-syn can also trigger dopamine neurons of the substantia nigra to express MHC class I that activate CD8+ T cells, which then kill neurons presenting the appropriate combination of MHC class I and peptide. IFNγ, interferon gamma; TCR, T-cell receptor. This figure was drawn by Noelle Burgess. Copyright JHU/ICE. Permission granted by JHU/ICE.

Tables

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    TABLE 1

    Commonly used pharmacological agents to treat symptoms of Parkinson disease

    Adapted from Armstrong and Okun (2020) and Seppi et al. (2019).

    SymptomMechanism of ActionMedicationFDA-Approved Indication for PD or Off Label
    Motor symptomsCore PD symptomsDA precursorIR carbidopa-levodopaFDA approved
    CR carbidopa-levodopaFDA approved
    ER carbidopa-levodopaFDA approved
    Core PD symptoms and motor fluctuationsNonergot DA agonistsPramipexoleFDA approved
    RopiniroleFDA approved
    RotigotineFDA approved
    Monoamine oxidase-B inhibitorsSelegilineFDA approved
    RasagilineFDA approved
    SafinamideFDA approved
    ZonisamideOff label
    Motor fluctuationsCatechol-O-methyltransferase inhibitorsEntacaponeFDA approved
    OpicaponeFDA approved
    Adenosine A2A receptor antagonistIstradefyllineFDA approved
    Rescue medicationLevodopa formulationInhaled carbidopa/levodopaFDA approved
    Nonergot dopamine agonistSublingual apomorphineFDA approved
    Injectable apomorphineFDA approved
    DyskinesiasNoncompetitive NMDA receptor antagonistIR amantadineFDA approved
    ER amantadine capsule/tabletFDA approved
    AnticholinergicsTrihexyphenidylFDA approved
    BenztropineFDA approved
    Nonmotor symptomsCognitive changesAcetylcholinesterase inhibitorsRivastigmineFDA approved
    DonepezilOff label
    GalantamineOff label
    NMDA receptor antagonistMemantineOff label
    PsychosisD2 and 5-HT2 receptor antagonistQuetiapineOff label
    ClozapineOff label
    5-HT2A and 5-HT2C receptor agonist and antagonistPimavanserinFDA approved
    Depression and anxietyTricyclic antidepressantsNortriptylineOff label
    AmitriptylineOff label
    ImipramineOff label
    DesipramineOff label
    Selective serotonin reuptake inhibitor/serotonin norepinephrine inhibitorCitalopramOff label
    EscitalopramOff label
    SertralineOff label
    ParoxetineOff label
    VenlafaxineOff label
    Levodopa formulationsCarbidopa/levodopa formulationsOff labela
    DA precursorsPramipexoleOff labela
    RopiniroleOff labela
    RotigotineOff labela
    Insomnia/sleep disordersMelatonin receptor 1A agonistMelatoninSupplement
    DA precursorsControlled-release carbidopa/levodopaOff labela
    Orthostatic hypotensionFluid retentionSalt tabsSupplement
    DA2-receptor antagonistDomperidoneNot FDA approved
    α1-adrenergic receptor stimulatorMidodrineOff label
    Increased Na reabsorptionFludrocortisoneOff label
    Increased norepinephrineDroxidopaFDA approved
    Acetylcholinesterase inhibitorPyridostigmineOff label
    ConstipationAnionic surfactantDocusateOff label
    Stool bulkingFiberSupplement
    Mixes stool fat and waterPolyethylene glycolOff label
    Anorexia, nausea, vomitingDA2-receptor antagonistDomperidoneNot FDA approved
    VGNA and K channel blocker, GABA receptor enhancerZonisamideOff label
    DroolingAnticholinergicAtropine 1% ophthalmic drops under the tongueOff label
    GlycopyrrolateOff label
    Botulinum toxin BFDA approved
    UrinaryMuscarinic antagonistSolifenacinOff label
    β3-adrenergic agonistMirabegronOff label
    FatigueMonoamine oxidase-B inhibitorsRasagilineOff labela
    DA and NE reuptake inhibitorsMethylphenidateOff label
    DA reuptake inhibitorModafinilOff label
    PainNonergot dopamine agonistsRotigotineOff labela
    DA precursorCarbidopa/levodopa formulationsOff labela
    • CR, controlled release; ER, extended release; IR, immediate release; NE, norepinephrine; VGNA, voltage-gated sodium.

    • aThese medications are FDA-approved for treatment of PD, but they are often used to treat these PD-related symptoms off label.

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    TABLE 2

    Potential disease-modifying therapies with active clinical research

    Adapted from Dawson and Dawson (2019) and McFarthing et al. (2020).

    MechanismName of TherapeuticSponsorPhaseEnd Date: Expected or ActualRecruitment StatusClinicaltrials.gov ID NumberResultsa
    LRRK2 inhibitorsDenali-151Denali Therapeutics1bDec 2020Active, not recruitingNCT04056689Ongoing
    Denali-201Denali Therapeutics1bDec 2019CompletedNCT03710707Promising PR-1b
    FB-101/1ST-1021ST BiotherapeuticsIJun 2020RecruitingNCT04165837Ongoing
    Glucocerebrosidase: chemical chaperone to translocate mutant enzyme from the ER into lysosomesAmbroxolUniversity College, LondonIIMay 2018CompletedNCT02941822Promising
    (Mullin et al., 2020)
    AmbroxolLawson Health Research InstituteIIDec 2021RecruitingNCT02914366Ongoing
    LTI-291Allergen/Lysosomal TherapeuticsIOct 2018, Jun 2018CompletedNL7061, NL6574Promising PR-2c
    GBA gene therapy: copy of GBA1 gene delivered by AAV9PR001APrevail TherapeuticsIIJun 20207RecruitingNCT04127578Ongoing
    Glucocerebrosidase: block accumulation of the glucocerebrosidase substrate, glucosylceramideVenglustat (GZ/SAR402671)Genzyme, a Sanofi companyIIFeb 2024Active, not recruitingNCT02906020Not effective
    α-Synuclein monoclonal antibodies to lower α-synuclein concentrations and block cell-to-cell transmissionCinpanemab/BIIB054BiogenIIJun 2021Active, not recruitingNCT03318523Not effective
    Cinpanemab/BIIB054BiogenIJul 2021Active, not recruitingNCT03716570Not effective
    PrasinezumabHoffman-La Roche; Prothena Biosciences LimitedIIApr 2026Active, not recruitingNCT03100149Ongoing
    MEDI1341AstraZenecaIMay 2022RecruitingNCT04449484Ongoing
    MEDI1341AstraZenecaIApr 2021RecruitingNCT03272165Ongoing
    Lundbeck-Lu-AF-82422H. Lundbeck A/SIDec 2020RecruitingNCT03611569Ongoing
    UB-312United Neuroscience, Ltd., Centre for Human Drug Research, Netherlands, Worldwide Clinical TrialsIJun 2022Active, not recruitingNCT04075318Ongoing
    PD01aAffiris AGIMay 2014CompletedNCT01568099Promising
    (Volc et al., 2020)
    α-Synuclein inhibitors of pathologic α-synuclein aggregationENT-01EnterinIIbDec 2021RecruitingNCT04483479Ongoing
    PBT434Alterity TherapeuticICompletedU1111-1211-0052Promising
    abstract (Stamler et al., 2019)
    UCB 0599 (formerly NPT200-11)UCB PharmaIIOct 2023Not yet recruitingNCT04658186Ongoing
    Anle138bMODAG GmbHIJune 2021Not yet recruitingNCT04685265Ongoing
    c-Abl kinase inhibitionSPARC-K0706Sun PharmaIMay 2019CompletedNCT02970019Promising
    abstract (Goldfine et al., 2019)
    SPARC-K0706Sun PharmaIIMar 2023RecruitingNCT03655236Ongoing
    Novartis: nilotinibGeorgetownIIJul 2020Active, not recruitingNCT02954978Promising
    (Pagan et al., 2020)
    Novartis: nilotinibNorthwestern UniversityIISept 2019CompletedNCT03205488Not effective
    (Simuni et al., 2021)
    1ST Biotherapeutics, Inc.: FB-1011ST Biotherapeutics, Inc.IJun 2020RecruitingNCT04165837Ongoing
    GLP1 receptor agonist, decreases inflammationAmylin Pharmaceutical/AstraZeneca: exenatideUniversity College, LondonIIISept 2023RecruitingNCT04232969/ ISRCTN14552789Ongoing
    ExenatideCenter for Neurology, StockholmIIOct 2022RecruitingNCT04305002Ongoing
    SR-ExenatidePeptron, Inc.IIDec 2021RecruitingNCT04269642Ongoing
    ExenatideUniversity of FloridaIMay 2021Active, not RecruitingNCT03456687Ongoing
    Novo Nordisk: liraglutideCedars-Sinai Medical CenterIIDec 2021Active, not recruitingNCT02953665Ongoing
    Sanofi: lixisenatideUniversity Hospital, ToulouseIIDec 2021Active, Not recruitingNCT03439943Ongoing
    Neuraly: NLY01/1ST Biotherapeutics 103Neuraly, Inc.IIAug 2022RecruitingNCT04154072Ongoing
    SemaglutideIIDec 2024Not yet recruitingNCT03659682Ongoing
    AntioxidantsDeferiproneImperial College LondonIIDec 2014CompletedNCT01539837Promising
    (Martin-Bastida et al., 2017)
    DeferiproneApoPharmaIISept 2019CompletedNCT02728843Unknown
    DeferiproneUniversity Hospital, LilleIIIOct 2011CompletedNCT00943748Promising
    (Grolez et al., 2015)
    DeferiproneUniversity Hospital, LilleIIApr 2021Active, not recruitingNCT02655315Ongoing
    HydrogenStone Brook UniversityII/IIIJuly 2022RecruitingNCT03971617Ongoing
    BotanicalsDA-9805Dong-A ST Co., Ltd.IIApr 2019CompletedNCT03189563Unknown
    WIN-1001XMedi Help LineIIDec 2020RecruitingNCT04220762Ongoing
    LingzhiXuanwu Hospital, BeijingIIIDec 2020RecruitingNCT03594656Ongoing
    Cell therapyIPS-NSC cellsAllife Medical Science and Technology Co., LtdIFeb 2021Not yet recruitingNCT03815071Ongoing
    Energy and mitochondriaUDCASheffield Teaching Hospitals NHS Foundation TrustIINov 2020Active, not recruitingNCT03840005Ongoing
    EPI-589PTC TherapeuticsIIApr 2019CompletedNCT02462603Unknown
    CNM_Au8Clene NanomedicineIIJuly 2021RecruitingNCT03815916Ongoing
    Microbiome/GITRifaximinUniversity of California, San FranciscoI/IIJun 2021RecruitingNCT03575195Ongoing
    RifaximinTaipei Medical University Shuang Ho HospitalI/IIDec 2020RecruitingNCT03958708Ongoing
    Fecal microbial transplantSoroka University Medical CenterII/IIIJun 2020CompletedNCT03876327Unknown
    Fecal microbial transplantUniversity of Texas Health Science Center, HoustonIDec 2020RecruitingNCT03671785Ongoing
    Resistant maltodextrinNorthwestern UniversityIIJun 2021RecruitingNCT03667404Ongoing
    Neurotrophic factorAAV2-GDNFNINDSIFeb 2022Active, not recruitingNCT01621581Ongoing
    AAV2-GDNFBrain Neurotherapy, Inc.IJun 2026RecruitingNCT04167540Ongoing
    Cerebral dopamine neurotrophic factorHerantis Pharma Plc.I/IIDec 2019CompletedNCT03295786Unknown
    Targeting α-synucleinAnle138bMODAG GmbHIJun 2021Not yet recruitingNCT04685265Ongoing
    MannitolHadassah Medical OrganizationIIDec 2020RecruitingNCT03823638Ongoing
    MemantineWayne State UniversityIIIJul 2023RecruitingNCT03858270Ongoing
    LRRK2 ASOBIIB094Biogen; Ionis PharmaceuticalsIDec 2022RecruitingNCT03976349Ongoing
    Inhibits ferroptosisCu(II)ATSMCollaborative Medicinal Development Pty LimitedIFeb 2020CompletedNCT03204929Promising
    abstract (Evans et al.)
    Young plasma infusionsStanford UniversityIDec 2019CompletedNCT02968433Promising
    (Parker et al., 2020)
    Young plasma infusionsThe Neurology CenterIVAug 2019CompletedNCT04202757Unknown
    SargramostimUniversity of NebraskaIDec 2022RecruitingNCT03790670Ongoing
    TerazosinJordan Schultz, University of IowaI/IIAug 2020Enrolling by invitationNCT03905811Ongoing
    TerazosinCedars-Sinai Medical CenterIIMar 2023RecruitingNCT04386317Ongoing
    GRF6021Alkahest, Inc.IIJul 2020CompletedNCT03713957Promising
    abstract
    (Rawner et al.)
    Electron chain transporterIdebenoneSecond Affiliated Hospital, SOM, Zhejiang UnivII/IIIJan 2023RecruitingNCT04152655Ongoing
    Mitochondrial supportMetabolic cofactor supplementationIstanbul Medipol Univiversity HospitalIISept 2020RecruitingNCT04044131Ongoing
    SimvastatinUniversity Hospital Plymouth NHS TrustIIAug 2020Active, not recruitingNCT02787590Ongoing
    • aOngoing studies are those that are recruiting or active; promising studies are those that will be or should be moving to the next phase of testing based on either a press release, abstract, or published journal article.

    • bPR-1: https://www.globenewswire.com/news-release/2020/08/06/2074205/0/en/Denali-Therapeutics-Announces-Decision-to-Advance-DNL151-into-Late-Stage-Clinical-Studies-in-Parkinson-s-Patients.html. Based on press releases and subsequent decisions by the company to move forward.

    • cPR-2: https://parkinsonsnewstoday.com/2020/10/06/bial-acquires-parkinsons-treatment-lti-291-opens-us-research-center/. Press release saying Bial pharma has purchased drug and plans to move it forward. Recent press releases indicate this approach was determined to be not effective: https://www.michaeljfox.org/news/news-context-two-study-outcomes-disappoint-parkinsons-pipeline-remains-strong.

    • GIT, gastrointestinal tract; ASO, antisense oligonucleotide; NSC, neuronal stem cell; PR, press release; UDCA, Ursodeoxycholic acid.

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Pharmacological Reviews: 73 (4)
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1 Oct 2021
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Review ArticleReview Article

Parkinson Disease Molecular Mechanisms and Neuroprotection

Sheila K. Pirooznia, Liana S. Rosenthal, Valina L. Dawson and Ted M. Dawson
Pharmacological Reviews October 1, 2021, 73 (4) 1204-1268; DOI: https://doi.org/10.1124/pharmrev.120.000189

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Review ArticleReview Article

Parkinson Disease Molecular Mechanisms and Neuroprotection

Sheila K. Pirooznia, Liana S. Rosenthal, Valina L. Dawson and Ted M. Dawson
Pharmacological Reviews October 1, 2021, 73 (4) 1204-1268; DOI: https://doi.org/10.1124/pharmrev.120.000189
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. Current Treatment Is Symptomatic
    • III. Challenges to the Identification of Disease-Modifying Therapies
    • IV. Biomarkers
    • V. Genetics of Parkinson Disease
    • VI. Environmental Contributors to Disease Progression
    • VII. Targeting Pathways that Promote Clearance of α-Synuclein
    • VIII. Mitochondrial Pathways to Neuroprotection
    • IX. Mitochondrial-Based Therapeutic Approaches
    • X. Interventions to Counter α-Synuclein Toxicity
    • XI. Therapeutic Avenues from Neuroinflammatory Pathways
    • XII. Targeting Altered Protein Translation
    • XIII. Maintenance of Neural Calcium Homeostasis for Neuroprotection
    • XIV. Regulation of Neuronal Oxidative and Nitrosative Stress
    • XV. Repairing Defects in Synaptic Dysfunctions
    • XVI. Neurotrophic Factors May Repair Dopaminergic Neurons
    • XVII. Conclusion
    • Acknowledgments
    • Authorship Contributions
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    • Abbreviations
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