CoChat
Sign Up
Cited by 99Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanismsinterferon and immune responses

Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology

Open access
Tresse, Emilie, Marturia-Navarro, Joana, Sew, Wei Qi Guinevere, Cisquella-Serra, Marina, Jaberi, Elham, Riera-Ponsati, Lluis, Fauerby, Natasha, Hu, Erling +3 more·2023·Molecular Psychiatry
DOI 10.1038/s41380-023-02251-4PMC PMC10914608
Open this paper in CoChat — free accountOpen PDF

Abstract

In the field of neurodegenerative diseases, especially sporadic Parkinson’s disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling ( Ifnb –/– / Ifnar –/– mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41380-023-02251-4

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients with clinical PD possess an increased accumulation of mtDNA mutations in blood cells.

    “recent studies have shown that patients with clinical PD possess an increased accumulation of mtDNA mutations in blood cells (Qi et al. 2023; Tresse et al. 2023)”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Tresse et al. 2023

    The Discussion reports an increased presence of mtDNA mutations in patients with PD, and the Results describe mtDNA alterations in PD brain samples. Neither passage establishes that the mutations accumulate in blood cells; searches for blood cells and peripheral blood did not find that finding in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 71

  1. [1]Mhyre TR Boyd JT Hamill RW Maguire-Zeiss KA Parkinson’s disease Subcell Biochem 2012 65 389 455 23225012 PMC4372387
  2. [2]Maday S Twelvetrees AE Moughamian AJ Holzbaur EL Axonal transport: cargo-specific mechanisms of motility and regulation Neuron 2014 84 292 309 25374356 PMC4269290
  3. [3]Crotty P Sangrey T Levy WB Metabolic energy cost of action potential velocity J Neurophysiol 2006 96 1237 46 16554507
  4. [4]Attwell D Laughlin SB An energy budget for signaling in the grey matter of the brain J Cereb Blood Flow Metab 2001 21 1133 45 11598490
  5. [5]Polymeropoulos MH Lavedan C Leroy E Ide SE Dehejia A Dutra A Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease Science 1997 276 2045 7 9197268
  6. [6]Kitada T Asakawa S Hattori N Matsumine H Yamamura Y Minoshima S Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism Nature 1998 392 605 8 9560156
  7. [7]Zimprich A Biskup S Leitner P Lichtner P Farrer M Lincoln S Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron 2004 44 601 7 15541309
  8. [8]Zimprich A Muller-Myhsok B Farrer M Leitner P Sharma M Hulihan M The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval Am J Hum Genet 2004 74 11 9 14691730 PMC1181898
  9. [9]Langston JW Schule B Rees L Nichols RJ Barlow C Multisystem Lewy body disease and the other parkinsonian disorders Nat Genet 2015 47 1378 84 26620112
  10. [10]Bonifati V Rizzu P van Baren MJ Schaap O Breedveld GJ Krieger E Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism Science 2003 299 256 9 12446870
  11. [11]Sazer S Sherwood SW Mitochondrial growth and DNA synthesis occur in the absence of nuclear DNA replication in fission yeast J Cell Sci 1990 97 509 16 2074269
  12. [12]Chapman J, Ng YS, Nicholls TJ. The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes. Life (Basel). 2020;10:164. PMC7555930 32858900
  13. [13]Goldsmith J Ordureau A Harper JW Holzbaur ELF Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons Neuron 2022 110 967 76.e8 35051374 PMC8930448
  14. [14]Bender A Krishnan KJ Morris CM Taylor GA Reeve AK Perry RH High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease Nat Genet 2006 38 515 7 16604074
  15. [15]Nido GS Dolle C Flones I Tuppen HA Alves G Tysnes OB Ultradeep mapping of neuronal mitochondrial deletions in Parkinson’s disease Neurobiol Aging 2018 63 120 7 29257976
  16. [16]Blackinton J Kumaran R van der Brug MP Ahmad R Olson L Galter D Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease Neurosci Lett 2009 452 8 11 19146923 PMC2640439
  17. [17]Papa S Petruzzella V Scacco S Sardanelli AM Iuso A Panelli D Pathogenetic mechanisms in hereditary dysfunctions of complex I of the respiratory chain in neurological diseases Biochim Biophys Acta 2009 1787 502 17 19210954
  18. [18]Kapsa RM Jean-Francois MJ Lertrit P Weng S Siregar N Ojaimi J Mitochondrial DNA polymorphism in substantia nigra J Neurol Sci 1996 144 204 11 8994125
  19. [19]Lin MT Cantuti-Castelvetri I Zheng K Jackson KE Tan YB Arzberger T Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease Ann Neurol 2012 71 850 4 22718549 PMC3383820
  20. [20]Reeve AK Krishnan KJ Turnbull DM Age related mitochondrial degenerative disorders in humans Biotechnol J. 2008 3 750 6 18512864
  21. [22]Hwang M, Bergmann CC. Neuronal Ablation of Alpha/Beta Interferon (IFN-alpha/beta) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-gamma Responsiveness in Microglia/Macrophages. J Virol. 2020;94:e00422–20. PMC7527041 32796063
  22. [23]Svennerholm B Ziegler R Lycke E Herpes simplex virus infection of the rat sensory neuron. Effects of interferon on cultured cells Arch Virol 1989 104 153 6 2538109
  23. [24]Jakimovski D, Kolb C, Ramanathan M, Zivadinov R, Weinstock-Guttman B. Interferon beta for Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018;8:a032003. PMC6211378 29311124
  24. [25]Inacio AR Liu Y Clausen BH Svensson M Kucharz K Yang Y Endogenous IFN-beta signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia J Neuroinflamm 2015 12 211 PMC4652356 26581581
  25. [26]Liu H Xin L Chan BP Teoh R Tang BL Tan YH Interferon-beta administration confers a beneficial outcome in a rabbit model of thromboembolic cerebral ischemia Neurosci Lett 2002 327 146 8 12098656
  26. [27]Ejlerskov P Hultberg JG Wang J Carlsson R Ambjorn M Kuss M Lack of Neuronal IFN-beta-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia Cell 2015 163 324 39 26451483 PMC4601085
  27. [28]Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, et al. PIAS2-mediated blockade of IFN-beta signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry. 2021;26:6083–99. PMC8758491 34234281
  28. [29]Villanueva EB, Tresse E, Liu Y, Duarte JN, Jimenez-Duran G, Ejlerskov P, et al. Neuronal TNFalpha, not alpha-syn, underlies PDD-like disease progression in IFNbeta-KO mice. Ann Neurol. 2021;90:789–807. 34476836
  29. [30]Tresse E Riera-Ponsati L Jaberi E Sew WQG Ruscher K Issazadeh-Navikas S IFN-beta rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1 EMBO J 2021 40 e106868 33913175 PMC8167366
  30. [31]Shahni R Cale CM Anderson G Osellame LD Hambleton S Jacques TS Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission Brain 2015 138 2834 46 26122121 PMC5808733
  31. [32]Park HJ Jang GY Kim YS Park JH Lee SE Vo MC A novel TLR4 binding protein, 40S ribosomal protein S3, has potential utility as an adjuvant in a dendritic cell-based vaccine J Immunother Cancer 2019 7 60 30819254 PMC6394096
  32. [33]Li L Ji B Zhao T Cui X Chen J Wang Z The structural changes of gray matter in Parkinson disease patients with mild cognitive impairments PLoS ONE 2022 17 e0269787 35857782 PMC9299333
  33. [34]Pereira JB Svenningsson P Weintraub D Bronnick K Lebedev A Westman E Initial cognitive decline is associated with cortical thinning in early Parkinson disease Neurology 2014 82 2017 25 24808018 PMC4105257
  34. [35]Jaberi E Tresse E Gronbaek K Weischenfeldt J Issazadeh-Navikas S Identification of unique and shared mitochondrial DNA mutations in neurodegeneration and cancer by single-cell mitochondrial DNA structural variation sequencing (MitoSV-seq) EBioMedicine 2020 57 102868 32629384 PMC7334819
  35. [36]Perez-Gonzalez R Gauthier SA Kumar A Saito M Saito M Levy E A Method for Isolation of Extracellular Vesicles and Characterization of Exosomes from Brain Extracellular Space Methods Mol Biol 2017 1545 139 51. 27943212
  36. [37]Kim Y Kim HD Youn B Park YG Kim J Ribosomal protein S3 is secreted as a homodimer in cancer cells Biochem Biophys Res Commun 2013 441 805 8 24211576
  37. [38]Phillips NR Sprouse ML Roby RK Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: a multiplex real-time PCR assay Sci Rep. 2014 4 3887 24463429 PMC4894387
  38. [39]Ibarretxe-Bilbao N Ramirez-Ruiz B Tolosa E Marti MJ Valldeoriola F Bargallo N Hippocampal head atrophy predominance in Parkinson’s disease with hallucinations and with dementia J Neurol 2008 255 1324 31 18821043
  39. [40]Zarei M Ibarretxe-Bilbao N Compta Y Hough M Junque C Bargallo N Cortical thinning is associated with disease stages and dementia in Parkinson’s disease J Neurol Neurosurg Psychiatry 2013 84 875 81 23463873 PMC3717586
  40. [41]Bette S Zimmermann U Wissinger B Knipper M OPA1, the disease gene for optic atrophy type Kjer, is expressed in the inner ear Histochem Cell Biol 2007 128 421 30 17828551
  41. [42]Paulin-Levasseur M Chen G Lariviere C The 2G2 antibody recognizes an acidic 110-kDa human mitochondrial protein Histochem J 1998 30 617 25 9870762
  42. [43]Soubannier V McLelland GL Zunino R Braschi E Rippstein P Fon EA A vesicular transport pathway shuttles cargo from mitochondria to lysosomes Curr Biol 2012 22 135 41 22226745
  43. [44]MacMahon Copas AN McComish SF Fletcher JM Caldwell MA The Pathogenesis of Parkinson’s Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes? Front Neurol 2021 12 666737 34122308 PMC8189423
  44. [45]Huang LS Hong Z Wu W Xiong S Zhong M Gao X mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury Immunity 2020 52 475 86.e5 32164878 PMC7266657
  45. [46]Bueno M Zank D Buendia-Roldan I Fiedler K Mays BG Alvarez D PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses PLoS ONE 2019 14 e0218003 31170232 PMC6553779
  46. [47]Aarsland D Kurz MW The epidemiology of dementia associated with Parkinson disease J Neurol Sci 2010 289 18 22 19733364
  47. [48]Doty RL Olfaction in Parkinson’s disease and related disorders Neurobiol Dis 2012 46 527 52 22192366 PMC3429117
  48. [49]Hoglinger GU Alvarez-Fischer D Arias-Carrion O Djufri M Windolph A Keber U A new dopaminergic nigro-olfactory projection Acta Neuropathol 2015 130 333 48 26072303
  49. [50]Hemmi H Takeuchi O Kawai T Kaisho T Sato S Sanjo H A Toll-like receptor recognizes bacterial DNA Nature 2000 408 740 5 11130078
  50. [51]Zhang Y Lee AS Shameli A Geng X Finegood D Santamaria P TLR9 blockade inhibits activation of diabetogenic CD8+ T cells and delays autoimmune diabetes J Immunol 2010 184 5645 53 20393135
  51. [52]Caielli S Conforti-Andreoni C Di Pietro C Usuelli V Badami E Malosio ML On/off TLR signaling decides proinflammatory or tolerogenic dendritic cell maturation upon CD1d-mediated interaction with invariant NKT cells J Immunol 2010 185 7317 29 21078913
  52. [53]Shi M Liu C Cook TJ Bullock KM Zhao Y Ginghina C Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson’s disease Acta Neuropathol 2014 128 639 50. 24997849 PMC4201967
  53. [54]Kato H Lu Q Rapaport D Kozjak-Pavlovic V Tom70 is essential for PINK1 import into mitochondria PLoS ONE 2013 8 e58435 23472196 PMC3589387
  54. [55]Todkar K Chikhi L Desjardins V El-Mortada F Pepin G Germain M Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs Nat Commun 2021 12 1971 33785738 PMC8009912
  55. [56]Hegde V Wang M Deutsch WA Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGG1 Biochemistry 2004 43 14211 7 15518571
  56. [57]Hegde V Yadavilli S McLaughlin LD Deutsch WA DNA repair efficiency in transgenic mice over expressing ribosomal protein S3 Mutat Res 2009 666 16 22 19481675 PMC2746704
  57. [58]Wasner K Smajic S Ghelfi J Delcambre S Prada-Medina CA Knappe E Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation Mov Disord 2022 37 1405 15. 35460111
  58. [59]Palozzi JM, Hurd TR. The role of programmed mitophagy in germline mitochondrial DNA quality control. Autophagy. 2023;19:2817–18. PMC10472838 36803283
  59. [60]De Gaetano A, Solodka K, Zanini G, Selleri V, Mattioli AV, Nasi M, et al. Molecular Mechanisms of mtDNA-Mediated Inflammation. Cells. 2021;26;10:2898. PMC8616383 34831121
  60. [61]Hegde AN Ubiquitin-proteasome-mediated local protein degradation and synaptic plasticity Prog Neurobiol 2004 73 311 57 15312912
  61. [63]Fang C Mo F Liu L Du J Luo M Men K Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine Cell Mol Immunol 2021 18 2211 23. 32398808 PMC8429462
  62. [64]Fang R Jiang Q Guan Y Gao P Zhang R Zhao Z Golgi apparatus-synthesized sulfated glycosaminoglycans mediate polymerization and activation of the cGAMP sensor STING Immunity 2021 54 962 75.e8 33857420
  63. [65]Dolle C Flones I Nido GS Miletic H Osuagwu N Kristoffersen S Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease Nat Commun 2016 7 13548 27874000 PMC5121427
  64. [66]Lowes H Pyle A Santibanez-Koref M Hudson G Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment Mol Neurodegener 2020 15 10 32070373 PMC7029508
  65. [67]Pyle A Lowes H Brennan R Kurzawa-Akanbi M Yarnall A Burn D Reduced mitochondrial DNA is not a biomarker of depression in Parkinson’s disease Mov Disord 2016 31 1923 4 27753152
  66. [68]Sliter DA Martinez J Hao L Chen X Sun N Fischer TD Parkin and PINK1 mitigate STING-induced inflammation Nature 2018 561 258 62. 30135585 PMC7362342
  67. [70]Scudamore O Ciossek T Increased Oxidative Stress Exacerbates alpha-Synuclein Aggregation In Vivo J Neuropathol Exp Neurol 2018 77 443 53. 29718367
  68. [73]Duffy MF Collier TJ Patterson JR Kemp CJ Luk KC Tansey MG Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration J Neuroinflamm 2018 15 129 PMC5930695 29716614
  69. [75]Kim Y Kim HD Kim J Cytoplasmic ribosomal protein S3 (rpS3) plays a pivotal role in mitochondrial DNA damage surveillance Biochim Biophys Acta 2013 1833 2943 52. 23911537
  70. [76]Kim J Chubatsu LS Admon A Stahl J Fellous R Linn S Implication of mammalian ribosomal protein S3 in the processing of DNA damage J Biol Chem 1995 270 13620 9 7775413
  71. [77]Ahn EH Kim DW Shin MJ Kim YN Kim HR Woo SJ PEP-1-ribosomal protein S3 protects dopaminergic neurons in an MPTP-induced Parkinson’s disease mouse model Free Radic Biol Med 2013 55 36 45 23178948

Cited by

Sorted by citations

Authors
Tresse, E., Marturia-Navarro, J., Sew, W. Q. G., Cisquella-Serra, M., Jaberi, E., Riera-Ponsati, L., Fauerby, N., Hu, E., Kretz, O., Aznar, S., & Issazadeh-Navikas, S.
Affiliations
  • University of Copenhagen (DK)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Copenhagen University Hospital (DK)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2023-10-02
Volume
28
Issue
11
Pages
4902-4914
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-023-02251-4
PMC
PMC10914608
OpenAlex
W4387235331
Cited by
99
References
7
Citations by year
2026: 34 · 2025: 38 · 2024: 23 · 2023: 4
FWCI
16.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
Funders
  • European Commission (703217, HORIZON2020)
  • Lundbeckfonden (R359-2020-2658, R223‐2016‐849)
  • Danmarks Frie Forskningsfond
  • H. Lundbeck A/S
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
Parkinson's disease dementia, mitochondrial DNA damage, mitochondrial DNA deletions, type I interferon signaling, cytosolic DNA sensing, oxidative stress, extracellular vesicles, ribosomal protein S3, neurodegeneration, mitochondrial DNA release
MeSH terms
Animals, DNA, Mitochondrial, Humans, Mitochondria, Neurons, Parkinson Disease, Proteomics, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review