The mechanisms and roles of selective autophagy in mammals

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 167 - 185

Published: Oct. 27, 2022

Language: Английский

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Circuit Mechanisms of Parkinson’s Disease

Neuron, Journal Year: 2019, Volume and Issue: 101(6), P. 1042 - 1056

Published: March 1, 2019

Language: Английский

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NF-κB in biology and targeted therapy: new insights and translational implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 4, 2024

Abstract NF-κB signaling has been discovered for nearly 40 years. Initially, was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have that its role can be expanded to variety of mechanisms, biological processes, human diseases, treatment options. In this review, we first scrutinize the research process signaling, summarize composition, activation, regulatory mechanism signaling. We investigate interaction other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, TLR The physiological pathological states well intricate involvement inflammation, immune regulation, tumor microenvironment, are also explicated. Additionally, illustrate how is involved cancers, autoimmune cardiovascular metabolic neurological COVID-19. Further, discuss therapeutic approaches targeting IKK inhibitors, monoclonal antibodies, proteasome nuclear translocation DNA binding TKIs, non-coding RNAs, immunotherapy, CAR-T. Finally, provide an outlook field hope present stereoscopic, comprehensive will inform future clinical practice.

Language: Английский

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Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 129(10), P. 4539 - 4549

Published: Sept. 15, 2019

Parkinson's disease (PD) is a common neurodegenerative that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are features of PD. Previous studies revealed terazosin (TZ) enhances the activity phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis increasing cellular levels. Therefore, we asked whether enhancement PGK1 would change course In toxin-induced genetic PD models in mice, rats, flies, induced pluripotent stem cells, TZ increased brain slowed or prevented neuron loss. The drug dopamine partially restored motor function. Because prescribed clinically, also interrogated 2 distinct human databases. We found slower progression, decreased PD-related complications, frequency diagnoses individuals taking related drugs. These findings suggest enhancing may slow neurodegeneration

Language: Английский

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Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: March 14, 2019

Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and neurites, which are pathological hallmarks Parkinson's disease (PD). The contribution αSyn to PD well established, but the detailed mechanism remains obscure. Using model in aggregation primary neurons was seeded by exogenously added, preformed amyloid fibrils (PFF), we found that majority pathogenic (indicated serine 129 phosphorylated αSyn, ps-αSyn) membrane-bound associated with mitochondria. In contrast, only minuscule amount physiological mitochondrial bound. vitro, PFF displayed stronger binding purified mitochondria than did monomer, revealing preferential aggregated αSyn. This selective ps-αSyn accumulation confirmed other neuronal animal models do not require added and, more importantly, postmortem brain tissues patients suffering from neurodegenerative diseases (α-synucleinopathies). We also showed accompanied defects cellular respiration neurons, suggesting link dysfunction. Together, our results show that, contrary aggregates preferentially bind mitochondria, indicating dysfunction as common downstream for α-synucleinopathies. Our findings suggest plausible explaining formation peculiar morphology body reveal disrupting interaction between therapeutic target

Language: Английский

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Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(6), P. 346 - 362

Published: May 17, 2023

Language: Английский

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Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Aging Cell, Journal Year: 2020, Volume and Issue: 19(3)

Published: Feb. 12, 2020

Abstract A common hallmark of age‐dependent neurodegenerative diseases is an impairment adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling a vital pathway for dopaminergic (DAergic) neurogenesis and essential system during embryonic development aging, the most critical risk factor Parkinson's disease (PD). To date, there no known cause or cure PD. Here we focus on potential to reawaken impaired neurogenic niches rejuvenate repair aged PD brain. Specifically, highlight WβC ‐ in plasticity subventricular zone (SVZ), largest germinal region mature brain innervated by nigrostriatal DAergic terminals, mesencephalic aqueduct‐periventricular (Aq‐PVR) Wnt‐sensitive niche, which proximity SNpc harbors neural stem progenitor cells (NSCs) with potential. The cytosolic accumulation β‐catenin, enters nucleus associates T cell factor/lymphoid enhancer binding (TCF/LEF) transcription factors, leading Wnt target genes. Here, underscore dynamic interplay between innervation astroglial‐derived factors regulating WβC‐dependent key genes orchestrating NSC proliferation, survival, migration differentiation. Aging, inflammation oxidative stress synergize neurotoxin exposure “turning off” switch via down‐regulation nuclear erythroid‐2‐related 2/Wnt‐regulated signalosome, player maintenance antioxidant self‐defense mechanisms homeostasis. Harnessing WβC‐signalling can thus restore neurogenesis, microenvironment, promote neurorescue regeneration.

Language: Английский

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The emerging role of α-synuclein truncation in aggregation and disease

Journal of Biological Chemistry, Journal Year: 2020, Volume and Issue: 295(30), P. 10224 - 10244

Published: May 19, 2020

α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, multiple system atrophy. These may induce further αsyn misfolding propagation of a prion-like process. It unclear why initially misfolds, but growing literature suggests critical role partial proteolytic processing resulting various truncations the highly charged flexible carboxyl-terminal region. This review aims 1) summarize recent evidence disease-specific occur atrophy animal disease models; 2) provide mechanistic insights on how truncation amino carboxyl regions modulate propensity pathologically misfold; 3) compare experiments evaluating properties truncated forms models with implications for progression; 4) assess uniquely imparted upon truncation; 5) discuss pathways through which therapies targeted interrupt them. Cumulatively, it evident αsyn, particularly be augmented by dysfunctional proteostasis, dramatically potentiates modulated seeding activity. Therapeutic strategies experimental paradigms should operate under assumption likely occurring both initial progressive stages, preventing effective preventative strategy against inclusion formation. Neurodegenerative Alzheimer's (AD), (PD), dementia (LBD), are collectively leading cause worldwide devastating human economic costs (1Prince, M., Wimo, A., Guerchet, Ali, G.-C., Wu, Y.-T., Prina, (2015) World Alzheimer Report 2015. The Global Impact Dementia. An Analysis Prevalence, Incidence, Cost Trends, Disease International, London.Google Scholar, 2Erkkinen M.G. Kim M.-O. Geschwind M.D. Clinical neurology epidemiology major diseases.Cold Spring Harb. Perspect. Biol. 2018; 10 (28716886): a03311810.1101/cshperspect.a033118Crossref PubMed Scopus (154) Google Scholar). There currently exist no modifying slow or prevent onset these diseases (2Erkkinen Scholar), research needed understand underlying pathophysiologic processes goal identifying targets therapeutic strategies. Common most presence amyloidogenic aggregates comprised predominantly misfolded proteins origins (3Kovacs G.G. Molecular pathological classification diseases: turning towards precision medicine.Int. J. Mol. Sci. 2016; 17 (26848654): 18910.3390/ijms17020189Crossref (95) 4Jellinger K.A. Interaction between pathogenic disorders.J. Cell. Med. 2012; 16 (22176890): 1166-118310.1111/j.1582-4934.2011.01507.xCrossref (70) Scholar); typically classified based clinical presentations identity 140-residue, 14.46-kDa found within presynaptic region neurons central nervous system, where has important functions vesicle trafficking (5Bendor J.T. Logan T.P. Edwards R.H. function α-synuclein.Neuron. 2013; 79 (24050397): 1044-106610.1016/j.neuron.2013.09.004Abstract Full Text PDF (364) 6Weinreb P.H. Zhen W. Poon A.W. Conway Lansbury P.T. NACP, implicated learning, natively unfolded.Biochemistry. 1996; 35 (8901511): 13709-1371510.1021/bi961799nCrossref (1184) Misfolding this consequent intracellular formation hallmark class termed synucleinopathies, includes PD, LBD, (MSA) (7Halliday G.M. Holton J.L. Revesz T. Dickson D.W. Neuropathology variability patients synucleinopathies.Acta Neuropathol. 2011; 122 (21720849): 187-20410.1007/s00401-011-0852-9Crossref (243) isolated from pathologic, β-sheet–rich polymers assembled oligomers larger (8Araki K. Yagi N. Aoyama Choong C.-J. Hayakawa H. Fujimura Nagai Y. Goto Mochizuki type amyloidosis featuring accumulation amyloid α-synuclein.Proc. Natl. Acad. U. S. A. 2019; 116 (31427526): 17963-1796910.1073/pnas.1906124116Crossref (0) 9Spillantini Crowther R.A. Jakes R. Hasegawa M. Goedert filamentous bodies bodies.Proc. 1998; 95 (9600990): 6469-647310.1073/pnas.95.11.6469Crossref (2074) 10Spillantini Cairns N.J. Lantos P.L. Filamentous α-synuclein link bodies.Neurosci. Lett. 251 (9726379): 205-20810.1016/S0304-3940(98)00504-7Crossref 11Bengoa-Vergniory Roberts R.F. Wade-Martins Alegre-Abarrategui oligomers: new hope.Acta 2017; 134 (28803412): 819-83810.1007/s00401-017-1755-1Crossref (102) 12Cremades Cohen S.I.A. Deas E. Abramov A.Y. Chen Orte Sandal Clarke R.W. Dunne P. Aprile F.A. Bertoncini C.W. Wood N.W. Knowles T.P.J. Dobson C.M. Klenerman D. Direct observation interconversion normal α-synuclein.Cell. 149 (22632969): 1048-105910.1016/j.cell.2012.03.037Abstract (486) 13Iljina Garcia G.A. Horrocks M.H. Tosatto L. Choi M.L. Ganzinger Gandhi Cremades Kinetic model aggregation provides spreading.Proc. 113 (26884195): E1206-E121510.1073/pnas.1524128113Crossref contribute toxicity dysfunction along progression (11Bengoa-Vergniory 14Peelaerts Bousset Van der Perren Moskalyuk Pulizzi Giugliano den Haute C. Melki Baekelandt V. strains distinct synucleinopathies after local systemic administration.Nature. 2015; 522 (26061766): 340-34410.1038/nature14547Crossref (582) 15Froula J.M. Castellana-Cruz Anabtawi N.M. Camino J.D. S.W. Thrasher D.R. Freire Yazdi A.A. Fleming Kumita J.R. Volpicelli-Daley L.A. Defining species responsible phenotypes mice.J. Chem. 294 (31142553): 10392-1040610.1074/jbc.RA119.007743Abstract (33) In addition polymerization, harbors extensive post-translational modifications (PTMs), phosphorylation, truncation, ubiquination, nitration, sumoylation, others (16Anderson J.P. Walker D.E. Goldstein de Laat Banducci Caccavello R.J. Barbour Huang Kling Lee Diep Keim P.S. Shen X. Chataway Schlossmacher et al.Phosphorylation Ser-129 dominant modification familial sporadic disease.J. 2006; 281 (16847063): 29739-2975210.1074/jbc.M600933200Abstract (711) 17Liu C.-W. Giasson B.I. Lewis V.M. Demartino G.N. Thomas P.J. A precipitating proteasome aggregation: pathogenesis Parkinson 2005; 280 (15840579): 22670-2267810.1074/jbc.M501508200Abstract (190) 18Zhang Li roles diseases.Front. Neurosci. 13 (31057362): 38110.3389/fnins.2019.00381Crossref (13) consequences oligomeric fibrillar preclinical have been extensively studied reviewed elsewhere 19Wong Y.C. Krainc neurodegeneration: mechanism strategies.Nat. 23 (28170377): 1-1310.1038/nm.4269Crossref (275) 20Karpowicz Trojanowski J.Q. V.M.-Y. Transmission seeds disease: developments.Lab. Investig. 99 (30760864): 971-98110.1038/s41374-019-0195-zCrossref current difficult thwart once widespread due recruitment endogenous spread glial cells vicious cycle (20Karpowicz 21Sorrentino Z.A. Chakrabarty astrocytes: tracing homeostasis neurodegeneration disease.Acta 138 (30798354): 1-2110.1007/s00401-019-01977-2Crossref (4) more attractive target fibril mechanisms such as aberrant PTMs if early essential progression. Some shown vitro alter similar those (18Zhang 22Sorrentino Vijayaraghavan Gorion K.M. Riffe C.J. Strang K.H. Caldwell Physiological C-terminal inclusions.J. 293 (30327435): 18914-1893210.1074/jbc.RA118.005603Abstract (11) corollary vivo appearance oxidative stress impaired clearance demonstrable synucleinopathy tissue diseased (23Dias Junn Mouradian M.M. Parkinsons. Dis. 3 (24252804): 461-49110.3233/JPD-130230Crossref (706) 24Poewe Seppi Tanner Halliday Brundin Volkmann Schrag A.-E. Lang A.E. disease.Nat. Rev. Primers. (28332488): 1701310.1038/nrdp.2017.13Crossref (594) 25Arotcarena M.-L. Teil Dehay B. Autophagy synucleinopathy: overwhelmed defective machinery.Cells. 8 (31181865): 56510.3390/cells8060565Crossref Indeed, 90% being phosphorylated at 15–20% C-terminally extracts 26Li West Colla Pletnikova O. Troncoso J.C. Marsh Dawson T.M. Jäkälä Hartmann Price D.L. M.K. Aggregation promoting cellular process enhanced disease-linked mutations.Proc. 102 (15684072): 2162-216710.1073/pnas.0406976102Crossref (313) 27Kellie J.F. Higgs R.E. Ryder J.W. Major Beach T.G. Adler C.H. Merchant Knierman Quantitative measurement intact proteoforms post-mortem control mass spectrometry.Sci. Rep. 4 (25052239): 579710.1038/srep05797Crossref (65) 28Baba Nakajo Tu Tomita Nakaya Iwatsubo bodies.Am. Pathol. 152 (9546347): 879-884PubMed detrimental among PTMs, consistently demonstrated C-truncated self-assembles far readily than full-length (FL) even causing missense mutant (17Liu 29Murray I.V.J. Quinn S.M. Koppaka Axelsen Ischiropoulos Role carboxy-terminus vitro.Biochemistry. 2003; 42 (12859200): 8530-854010.1021/bi027363rCrossref (256) 30Crowther Spillantini Synthetic filaments α-synuclein.FEBS 436 (9801138): 309-31210.1016/S0014-5793(98)01146-6Crossref (323) 31Serpell L.C. Berriman Fiber diffraction synthetic shows amyloid-like cross-β conformation.Proc. 2000; 97 (10781096): 4897-490210.1073/pnas.97.9.4897Crossref (596) 32Mishizen-Eberz A.J. Norris E.H. Hodara Lynch Cleavage calpain: potential degradation fibrillized nitrated α-synuclein.Biochemistry. 44 (15909996): 7818-782910.1021/bi047846qCrossref 33Iyer Roeters S.J. Kogan Woutersen Claessens M.M.A.E. Subramaniam contain strongly twisted β-sheets.J. Am. Soc. 139 (28968082): 15392-1540010.1021/jacs.7b07403Crossref (35) 34Levitan Chereau Fink A.L. Anderson Millhauser G.L. Conserved charge exerts profound influence rate α-synuclein.J. 411 (21689664): 329-33310.1016/j.jmb.2011.05.046Crossref (56) 35Hoyer Cherny Jovin Rapid self-assembly observed situ atomic force microscopy.J. 2004; 340 (15184027): 127-13910.1016/j.jmb.2004.04.051Crossref (141) 36Hoyer acidic comprising acids 109-140 43 (15610017): 16233-1624210.1021/bi048453uCrossref (230) Proteolytic (32Mishizen-Eberz 37Sevlever Jiang Yen S.-H.C. Cathepsin D main lysosomal enzyme involved generation its carboxy-terminally species.Biochemistry. 2008; 47 (18702517): 9678-968710.1021/bi800699vCrossref (179) 38Tsujimura Taguchi Watanabe Tatebe Tokuda Mizuno Tanaka Lysosomal cathepsin B enhances aggregate forming activity exogenous fibrils.Neurobiol. 73 (25466281): 244-25310.1016/j.nbd.2014.10.011Crossref (31) 39McGlinchey R.P. Cysteine cathepsins 112 (26170293): 9322-932710.1073/pnas.1500937112Crossref (77) 40Mishizen-Eberz Guttmann Day Distinct cleavage patterns calpain I vitro.J. Neurochem. 86 (12887682): 836-84710.1046/j.1471-4159.2003.01878.xCrossref (115) 41Pieri Chafey Le Gall Clary G. Redeker Cellular response neuroblastoma fibrils, constituent bodies.Biochim. Biophys. Acta. 1860 (26468903): 8-1910.1016/j.bbagen.2015.10.007Crossref (14) 42Hossain Alim Takeda Kaji Shinoda Uéda Limited proteolysis NACP/α-synuclein.J. Alzheimers. 2001; (12214024): 577-58410.3233/jad-2001-3608Crossref (26) possibly promoted impairment proteostasis aging (43Kaushik Cuervo A.M. coming age chaperone-mediated autophagy.Nat. Cell 19 (29626215): 365-38110.1038/s41580-018-0001-6Crossref initiate pathology diverse types survey physiological their formation, functional context toxicity, was first synaptic vesicles Torpedo fish "synuclein" when homologous detected rat nuclear envelopes (44Maroteaux Campanelli Scheller Synuclein: neuron-specific localized nucleus nerve terminal.J. 1988; (3411354): 2804-281510.1523/JNEUROSCI.08-08-02804.1988Crossref majority cytoplasmic, soluble intrinsically disordered (6Weinreb association vesicles, repeat-rich N terminus (residues 1–60) "nonamyloid component" (NAC) domain 61–95) adopt helical structure necessary regulatory thought neuron (45Fusco De Simone Gopinath Vostrikov Vendruscolo Veglia three determine membrane-bound behaviour.Nat. Commun. 2014; 5 (24871041): 382710.1038/ncomms4827Crossref (207) 46Fusco Pape Stephens A.D. Mahou Costa A.R. Kaminski C.F. Schierle G.S. Structural basis assembly α-synuclein.Nat. 7 (27640673): 1256310.1038/ncomms12563Crossref (104) However, also maintenance SNARE assembly, evidenced ability mitigate CSPα null mice (47Chandra Gallardo Fernández-Chacón Schlüter O.M. Südhof T.C. cooperates neurodegeneration.Cell. 123 (16269331): 383-39610.1016/j.cell.2005.09.028Abstract (716) chaperone, made possible labile intermolecular interactions inherent unstructured (48Park Jung H.Y. T.D. Park J.H. Yang C.-H. N-terminal-binding C-terminal-solubilizing α-synuclein, molecular chaperone.J. 2002; 277 (12032141): 28512-2852010.1074/jbc.M111971200Abstract 49Souza Chaperone-like synucleins.FEBS 474 (10828462): 116-11910.1016/S0014-5793(00)01563-5Crossref (182) biological attributed overarching structural domains: amphipathic terminus, hydrophobic NAC, C 96–140). seven imperfect KTKEGV 11-mer repeats helix phospholipid surfaces NAC acts lipid "sensor," mediating specificity binding 45Fusco Last, remains nearly all conformations 15 residues; state ever-changing permits chaperone bind metals, polyamines, positively tau 48Park 50Oikawa Nonaka Terada Tamaoka Hisanaga S.-I. exhibit gain function, Tau inhibiting microtubule assembly.J. 291 (27226637): 15046-1505610.1074/jbc.M116.736355Abstract (41) 51Tuttle Comellas Nieuwkoop Covell D.J. Berthold D.A. Kloepper K.D. Courtney J.K. Barclay Kendall Wan Stubbs Schwieters C.D. V.M.Y. George al.Solid-state NMR Struct. (27018801): 409-41510.1038/nsmb.3194Crossref (432) Due largely nature (52Giasson Murray stretch 12 acid residues middle filament 276 (11060312): 2380-238610.1074/jbc.M008919200Abstract (644) confluence result disease-associated dense insoluble detergents Using digestion antibody accessibility, techniques cryo-EM, determined typical core composed roughly ∼31–102 stacked in-register β-sheets (31Serpell NM

Language: Английский

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Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases

Journal of Immunology Research, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 12

Published: March 23, 2022

Oxidative stress plays an important role in the development of aging-related diseases by accelerating lipid peroxidation polyunsaturated fatty acids cell membrane, resulting production aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many signaling pathways including regulation apoptosis signal transduction pathways. binding proteins to (4-HNE-protein) acts marker peroxidation, its increasing concentration brain tissues fluids because aging, ultimately gives rise some hallmark disorders, neurodegenerative (Alzheimer’s Parkinson’s diseases), ophthalmic (dry eye, macular degeneration), hearing loss, cancer. This review aims describe physiological origin 4-HNE, elucidate toxicity diseases, discuss detoxifying effect aldehyde dehydrogenase glutathione 4-HNE-driven diseases.

Language: Английский

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Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound

Nature Biomedical Engineering, Journal Year: 2022, Volume and Issue: 7(2), P. 149 - 163

Published: Dec. 1, 2022

Language: Английский

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