Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: April 3, 2018

Exosomes are cell-derived nanovesicles (50-150 nm), which mediate intercellular communication, and candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, lack methods to create designer exosomes have hampered their development into interventions. Here, we report a set EXOsomal transfer cells (EXOtic) devices that enable efficient, customizable production in engineered mammalian cells. These genetically encoded exosome producer enhance production, specific mRNA packaging, delivery the cytosol target cells, enabling efficient cell-to-cell communication without need concentrate exosomes. Further, implanted living mice could consistently deliver cargo brain. Therapeutic catalase by attenuated neurotoxicity neuroinflammation vitro vivo models Parkinson's disease, indicating potential usefulness EXOtic for RNA delivery-based applications.

Language: Английский

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NAD+ in Brain Aging and Neurodegenerative Disorders

Cell Metabolism, Journal Year: 2019, Volume and Issue: 30(4), P. 630 - 655

Published: Oct. 1, 2019

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are synaptic plasticity neuronal resistance. Here, we review emerging findings that reveal key roles for related metabolites the adaptation of neurons to wide range physiological stressors counteracting processes neurodegenerative diseases, such as those occurring Alzheimer's, Parkinson's, Huntington amyotrophic lateral sclerosis. Advances understanding molecular mechanisms NAD+-based resilience will lead novel approaches facilitating healthy brain aging treatment neurological disorders. Nicotinamide adenine dinucleotide (NAD+) fundamental molecule health disease, it central several bioenergetic functions. synthesized via three major pathways, including de novo biosynthesis, Preiss-Handler pathway, salvage pathway (Figure 1). While aspartate most photosynthetic eukaryotes, kynurenine only synthetic mammals. The starts with catabolism amino acid tryptophan converted two steps intermediate kynurenine, which can generate NAD+, kynurenic acid, or xanthurenic (Vécsei et al., 2013Vécsei L. Szalárdy Fülöp F. Toldi J. Kynurenines CNS: recent advances new questions.Nat. Rev. Drug Discov. 2013; 12: 64-82Crossref PubMed Scopus (263) Google Scholar). modulates functions synthesis neurotransmitters (glutamate acetylcholine) well regulates N-methyl-D-aspartate (NMDA) receptor activity free radical production exhibits "double-edged sword" effects on both neuroprotective (tryptophan, picolinic acid) neurotoxic intermediates, 3-hydroxykynurenine (3-HK) generates radicals, 3-hydroxyanthranilic (3-HAA), quinolinic (that induces glutamate excitotoxicity) an NMDA antagonist, agonist ambient levels these determined by different enzymes, preferentially localized microglia astrocytes, suggesting necessary glial cell-neuron communication (Schwarcz Pellicciari, 2002Schwarcz R. Pellicciari Manipulation kynurenines: targets, effects, clinical opportunities.J. Pharmacol. Exp. Ther. 2002; 303: 1-10Crossref (399) synthesize from pyridine bases. synthesizes nicotinic (NA) (NAAD). One important step constitutes nicotinamide mononucleotide adenylyltransferases (NMNATs), also pathways. Three mammalian NMNATs exist, NMNAT1–3, showing mice D. melanogaster models (Ali 2013Ali Y.O. Li-Kroeger Bellen H.J. Zhai R.G. Lu H.C. NMNATs, evolutionarily conserved maintenance factors.Trends Neurosci. 36: 632-640Abstract Full Text PDF (0) NMNAT1 NMNAT3 ubiquitously expressed, NMNAT2 enriched brain, adequate seem be essential axon development survival (Gilley 2019Gilley Mayer P.R. Yu G. Coleman M.P. Low compromise survival.Hum. Mol. Genet. 2019; 28: 448-458Crossref (4) recycling (NAM) (NMN) intracellular phosphoribosyltransferase (iNAMPT), followed conversion NMN into (Bogan Brenner, 2008Bogan K.L. Brenner C. Nicotinic nicotinamide, riboside: evaluation precursor vitamins human nutrition.Annu. Nutr. 2008; 115-130Crossref (269) Scholar, Verdin, 2015Verdin E. NAD(+) aging, metabolism, neurodegeneration.Science. 2015; 350: 1208-1213Crossref (234) Additionally, riboside (NR) integrates this NR kinase 1 (NRK1) NRK2 (Bieganowski 2004Bieganowski P. Discoveries nutrient NRK genes establish independent route fungi humans.Cell. 2004; 117: 495-502Abstract (315) Ratajczak 2016Ratajczak Joffraud M. Trammell S.A. Ras Canela N. Boutant Kulkarni S.S. Rodrigues Redpath Migaud M.E. al.NRK1 controls metabolism cells.Nat. Commun. 2016; 7: 13103Crossref (82) Despite NAMPT being relatively highly expressed brown adipocyte, liver, kidney tissues compared tissue mice, studies have supported role iNAMPT (Stein Imai, 2014Stein L.R. Imai S. Specific ablation Nampt adult neural stem cells recapitulates their functional defects during aging.EMBO 2014; 33: 1321-1340PubMed Stein Wozniak D.F. Dearborn J.T. Kubota Apte R.S. Izumi Y. Zorumski C.F. Expression hippocampal cortical excitatory critical cognitive function.J. 34: 5800-5815Crossref Zhang 2010Zhang W. Xie Wang T. Bi Li H. L.Q. Ye S.Q. Ding Neuronal protective PBEF mouse model cerebral ischemia.J. Cereb. Blood Flow Metab. 2010; 30: 1962-1971Crossref (62) Experimental evidence suggests blood NA NAM able cross plasma membrane, while cannot taken up directly but needs smaller uncharged molecules enter (Hara 2007Hara Yamada K. Shibata Osago Hashimoto Tsuchiya Elevation NAD involvement cells.J. Biol. Chem. 2007; 282: 24574-24582Crossref (104) Extracellularly, digested membrane-bound CD38 CD157, further metabolized extracellular (eNAMPT); however, CD73 ways been proposed. First, converts CD73, presumptive nucleoside transporter (Fletcher 2017Fletcher Doig C.L. Oakey L.A. Callingham Da Silva Xavier Garten A. Elhassan Y.S. al.Nicotinamide kinases display redundancy mediating skeletal muscle cells.Mol. 2017; 6: 819-832Crossref (11) Grozio 2013Grozio Sociali Sturla Caffa I. 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A single responsible cyclization, hydrolysis, base-exchange chemistries.Biochemistry. 1998; 37: 13239-13249Crossref (83) Third, has reported (Grozio 2019Grozio Mills K.F. Yoshino Tokizane Lei Cunningham Sasaki al.Slc12a8 transporter.Nat. 1: 47-57Crossref (88) 2011Yoshino Yoon M.J. mononucleotide, intermediate, treats pathophysiology diet- age-induced diabetes mice.Cell 14: 528-536Abstract (442) newly transporter, Slc12a8, regulated murine small intestine, Slc12a8 deficiency abrogates uptake vitro vivo These pathways detailed Figure 1. Studies humans indicate supplementation dramatically upregulates NAAD, unknown metabolic possibilities NAAD and/or (NAMN) (Trammell 2016aTrammell Schmidt M.S. Weidemann B.J. Jaksch Dellinger R.W. Z. Abel E.D. uniquely orally bioavailable humans.Nat. 12948Crossref (131) Thus, although intensively characterized long time, there remaining determined. vital redox cofactor ATP production, substrate at least four families healthspan longevity (Fang 2017Fang E.F. Lautrup Hou Y.J. Demarest T.G. Croteau D.L. Mattson Bohr V.A. aging: translational implications.Trends Med. 899-916Abstract Gomes 2013Gomes A.P. Price N.L. Ling A.J. Moslehi J.J. Montgomery M.K. Rajman White J.P. Teodoro J.S. Wrann C.D. Hubbard B.P. al.Declining pseudohypoxic state disrupting nuclear-mitochondrial aging.Cell. 155: 1624-1638Abstract (529) plays glycolysis citric (TCA) cycle, its ability accept hydride equivalents, forming NADH (Krebs, 1970Krebs H.A. Rate control tricarboxylic cycle.Adv. Enzyme Regul. 1970; 8: 335-353Crossref Wallace, 2012Wallace D.C. Mitochondria cancer.Nat. Cancer. 2012; 685-698Crossref (853) one electron donors oxidative phosphorylation (OXPHOS) mitochondria, providing electrons transport chain (ETC) ratio NAD+/NADH various reactions compartments, increased influence homeostasis changes (Ying, 2008Ying NADP+/NADPH death: regulation biological consequences.Antioxid. Redox Signal. 10: 179-206Crossref (649) functions, antioxidation generation stress, calcium death In addition NAD+-consuming proteins, catabolize NAM. They class III histone deacetylases sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), ADP ribosyl-cyclases (CD38/CD157), NADase sterile alpha TIR motif-containing (SARM1) mammals, seven SIRTs, regulate large number survival, rejuvenation, cancer, (Chalkiadaki Guarente, 2015Chalkiadaki Guarente multifaceted 15: 608-624Crossref (150) SIRTs spectrum disease 2000Imai Armstrong C.M. Kaeberlein Transcriptional silencing Sir2 NAD-dependent deacetylase.Nature. 2000; 403: 795-800Crossref (2280) For example, SIRT1 consumes glycolysis, gluconeogenesis, balance between biogenesis mitophagy responses exercise metabolic/excitatory challenges (Bonkowski Sinclair, 2016Bonkowski Sinclair D.A. Slowing ageing design: rise sirtuin-activating compounds.Nat. Cell 17: 679-690Crossref Cheng 2016Cheng Yang Zhou Maharana Peng Liu Wan Marosi Misiak al.Mitochondrial SIRT3 mediates challenges.Cell 128-142Abstract (98) Fang, 2019Fang Mitophagy inhibit Alzheimer disease.Autophagy. 1112-1114Crossref (2) Furthermore, shown promote neurite outgrowth development, regulating dendritic arborization, long-term potentiation learning, memory (Gao 2010Gao W.Y. Mao Y.W. Gräff Guan Pan Mak Kim Su S.C. Tsai L.H. miR-134.Nature. 466: 1105-1109Crossref (585) Among 17 PARPs, them capable adding multiple ADP-ribose units (poly[ADP-ribosyl]ation) PARylation; they PARP1, PARP2, PARP5a (tankyrase 1), PARP5b 2) (Leung, 2017Leung A.K.L. PARPs.Curr. 27: R1256-R1258Abstract Rouleau 2010Rouleau Patel Hendzel Kaufmann S.H. Poirier G.G. PARP inhibition: PARP1 beyond.Nat. 293-301Crossref (813) supports transfers first moiety lysine, arginine, glutamate, aspartate, serine residues acceptor protein, preceding ones, thereby poly(ADP-ribose) (PAR) chains (Bonfiglio 2017Bonfiglio Fontana Q. Colby Gibbs-Seymour Atanassov Bartlett Zaja Ahel Matic Serine ADP-ribosylation depends HPF1.Mol. Cell. 940: 932-940Abstract Daniels 2014Daniels Ong S.E. Leung A.K. Phosphoproteomic approach characterize mono- poly(ADP-ribosyl)ation sites Proteome Res. 13: 3510-3522Crossref (74) majority PARylation executed participates processes, DNA repair, DNA/RNA response. PAR serving signaling scaffolding element 2016bFang Scheibye-Knudsen Chua Nuclear damage signalling mitochondria ageing.Nat. 308-321Crossref Leung, Scholar), e.g., stabilization repair forks, catalytic single-strand breaks, bulky lesions, double-strand breaks (DSBs) (Ray Chaudhuri Nussenzweig, 2017Ray Nussenzweig chromatin remodelling.Nat. 18: 610-621Crossref (33) However, excessive activation trigger death, termed parthanatos, formation triggers release apoptosis-inducing factor (AIF) cytosolic side outer membrane. AIF then translocated nucleus activate macrophage migration inhibitory (MIF, nuclease), finally results MIF-dependent chromatinolysis (Wang 2011Wang N.S. Haince J.F. Kang David K.K. Andrabi Dawson T.M. Poly(ADP-ribose) binding polymerase-1-dependent (parthanatos).Sci. 4: ra20Crossref (198) 2016Wang An Umanah G.K. Park Nambiar Eacker S.M. B. Bao Harraz M.M. Chang al.A nuclease induced polymerase-1.Science. 354Crossref (65) 2002Yu S.W. Poitras M.F. Coombs Bowers W.J. Federoff Mediation factor.Science. 297: 259-263Crossref (1386) Notably, depletion PAR-dependent hexokinase activity, resulting dysfunctional likely (Andrabi 2014Andrabi Stevens Karuppagounder Gagné polymerase-dependent energy occurs glycolysis.Proc. Natl. Acad. Sci. USA. 111: 10209-10214Crossref (128) Fouquerel 2014Fouquerel Goellner E.M. Barbi Moura Feinstein Wheeler Romero al.ARTD1/PARP1 negatively inhibiting depletion.Cell Rep. 1819-1831Abstract loss, hyperactivation PARP1-induced induce loss accelerated 2016aFang Kassahun Shamanna Kalyanasundaram Bollineni R.C. Wilson M.A. al.NAD(+) replenishment improves lifespan ataxia telangiectasia repair.Cell 24: 566-581Abstract view detrimental endogenous exogenous excitotoxicity, ischemia-reperfusion injury, inflammation-induced (Yu Scholar) targeting provide therapeutic strategies diseases. catalyzes Ca2+-responsive messenger cyclic (cADPR) use immunity, inflammation, even social behaviors (Jin 2007Jin H.X. Hirai Torashima Nagai Lopatina O. Shnayder N.A. Noda Seike behaviour oxytocin secretion.Nature. 446: 41-45Crossref (395) type II form (i.e., C-terminal) (with domain facing cytosol) (Liu 2017Liu Zhao W.H. Y.N. Z.Y. Fang S.L. Cytosolic interaction CIB1 levels.Proc. 2008Liu Graeff Kriksunov I.A. Lam Hao Conformational closure site (dagger) (double dagger).Biochemistry. 47: 13966-13973Crossref age-dependent increase CD38, contribute impaired function lymphocyte differentiation antigen, (Mizuguchi 1995Mizuguchi Otsuka Sato Ishii Kon Nishina Katada Ikeda localization antigen brain.Brain 1995; 697: 235-240Crossref (57) knockout show significant protection against ischemic (Long 2017Long J.H. Klimova Fowler Loane D.J. Kristian despite high level poly-ADP-ribosylation.Neurochem. 42: 283-293Crossref (1) SARM1 recognized cleaves ADPR, cADPR domain. It non-brain tissues, liver (Essuman 2017Essuman Summers D.W. X. DiAntonio Milbrandt toll/interleukin-1 possesses intrinsic cleavage promotes pathological axonal degeneration.Neuron. 93: 1334-1343Abstract (18) An, 2018Pan Z.G. X.S. deletion restrains NAFLD fat diet (HFD) reducing lipid accumulation.Biochem. Biophys. 2018; 498: 416-423Crossref (7) cyclase glycohydrolase activities, estimated Michaelis constant (Km) 24 μM, similar other known NAD+-consumers (PARP1, 50–97 μM; SIRT1, 94–96 15–25 μM) (Cantó 2015Cantó Menzies K.J. Auwerx homeostasis: balancing act nucleus.Cell 22: 31-53Abstract degeneration therefore potential target intervention holds signal, clear. SIRTS, CD38/CD157, compete each consume NAD+; thus, enzyme impair activities enzymes. interrelationships reviewed recently equilibrium synthesis, consumption, cytoplasm, nucleus, Golgi apparatus. Two expression subcellular-specific NAD+-synthetic transporters metabolites. convert NAD+. include

Language: Английский

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CSF and blood biomarkers for Parkinson's disease

The Lancet Neurology, Journal Year: 2019, Volume and Issue: 18(6), P. 573 - 586

Published: April 11, 2019

Language: Английский

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Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand

Cell Metabolism, Journal Year: 2018, Volume and Issue: 27(2), P. 439 - 449.e5

Published: Jan. 11, 2018

Language: Английский

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Intermittent metabolic switching, neuroplasticity and brain health

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(2), P. 81 - 94

Published: Jan. 11, 2018

Language: Английский

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The genetics of Parkinson disease

Ageing Research Reviews, Journal Year: 2017, Volume and Issue: 42, P. 72 - 85

Published: Dec. 26, 2017

Language: Английский

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Global Trends in the Incidence, Prevalence, and Years Lived With Disability of Parkinson's Disease in 204 Countries/Territories From 1990 to 2019

Frontiers in Public Health, Journal Year: 2021, Volume and Issue: 9

Published: Dec. 7, 2021

Background: Parkinson's disease (PD) is an increasing challenge to public health. Tracking the temporal trends of PD burden would inform health strategies. Methods: Data was obtained from Global Burden Disease 2019. Trends in incidence, prevalence, and years lived with disability (YLDs) were estimated using annual percentage change (EAPC) age-standardized rate (ASR) 1990 The EAPCs calculated ASR through a linear regression model. Results: overall YLDs increased 2019, their 0.61 (95% confidence interval [CI]: 0.58–0.65), 0.52 CI: 0.43–0.61), 0.53 0.44–0.62). largest number patients seen groups aged more than 65 years, rapidly population 80 years. Upward observed most settings over past 30 Incident pronouncedly United States America Norway, which respective 2.87 2.35–3.38) 2.14 2.00–2.29). Additionally, for prevalence 2.63 2.43–2.83) 2.61 2.41–2.80). However, decreasing appeared about countries, particularly Italy Republic Moldova. Conclusions: Increasing globally, regions countries Our findings suggested that control management should be strengthened, especially when considering aging tendency population.

Language: Английский

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Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(9), P. 2293 - 2293

Published: May 9, 2019

A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter expression plethora inflammatory mediators. These factors, in turn, initiate or contribute development processes. an important tool for study However, serotype, route administration, number injections this toxin induce varied responses. Thus, here, we review use models neurodegeneration well discuss neuroinflammatory mechanisms induced by could underpin events linked process.

Language: Английский

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Reversing a model of Parkinson’s disease with in situ converted nigral neurons

Nature, Journal Year: 2020, Volume and Issue: 582(7813), P. 550 - 556

Published: June 24, 2020

Language: Английский

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Disruption of mitochondrial complex I induces progressive parkinsonism

Nature, Journal Year: 2021, Volume and Issue: 599(7886), P. 650 - 656

Published: Nov. 3, 2021

Language: Английский

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