Astrocytic Changes in Mitochondrial Oxidative Phosphorylation Protein Levels in Parkinson's Disease.
mitochondria; OXPHOS; imaging mass cytometry; Parkinson's disease
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
07
10
2021
received:
04
08
2021
accepted:
14
10
2021
pubmed:
16
11
2021
medline:
18
3
2022
entrez:
15
11
2021
Statut:
ppublish
Résumé
Mitochondrial dysfunction within neurons, particularly those of the substantia nigra, has been well characterized in Parkinson's disease and is considered to be related to the pathogenesis of this disorder. Dysfunction within this important organelle has been suggested to impair neuronal communication and survival; however, the reliance of astrocytes on mitochondria and the impact of their dysfunction on this essential cell type are less well characterized. This study aimed to uncover whether astrocytes harbor oxidative phosphorylation (OXPHOS) deficiencies in Parkinson's disease and whether these deficiencies are more likely to occur in astrocytes closely associated with neurons or those more distant from them. Postmortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key OXPHOS proteins across all five complexes. We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age. Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could have an impact on their reactivity and ability to support neurons in Parkinson's disease.
Sections du résumé
BACKGROUND
Mitochondrial dysfunction within neurons, particularly those of the substantia nigra, has been well characterized in Parkinson's disease and is considered to be related to the pathogenesis of this disorder. Dysfunction within this important organelle has been suggested to impair neuronal communication and survival; however, the reliance of astrocytes on mitochondria and the impact of their dysfunction on this essential cell type are less well characterized.
OBJECTIVE
This study aimed to uncover whether astrocytes harbor oxidative phosphorylation (OXPHOS) deficiencies in Parkinson's disease and whether these deficiencies are more likely to occur in astrocytes closely associated with neurons or those more distant from them.
METHODS
Postmortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key OXPHOS proteins across all five complexes.
RESULTS
We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age.
CONCLUSION
Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could have an impact on their reactivity and ability to support neurons in Parkinson's disease.
Substances chimiques
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
302-314Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100540
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900652
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400074
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0502157
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
Références
Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1989;1(8649):1269.
Langston JW, Ballard PA Jr. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med 1983;309(5):310.
Kam TI, Hinkle JT, Dawson TM, Dawson VL. Microglia and astrocyte dysfunction in Parkinson's disease. Neurobiol Dis 2020;144:105028.
Booth HDE, Hirst WD, Wade-Martins R. The role of astrocyte dysfunction in Parkinson's disease pathogenesis. Trends Neurosci 2017;40(6):358-370.
Fossati G, Matteoli M, Menna E. Astrocytic factors controlling synaptogenesis: a team play. Cell 2020;9(10):2173-2193.
Fullana N, Gasull-Camos J, Tarres-Gatius M, Castane A, Bortolozzi A, Artigas F. Astrocyte control of glutamatergic activity: downstream effects on serotonergic function and emotional behavior. Neuropharmacology 2020;166:107914.
Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010;119(1):7-35.
Joe EH, Choi DJ, An J, Eun JH, Jou I, Park S. Astrocytes, microglia, and Parkinson's disease. Exp Neurobiol 2018;27(2):77-87.
He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 2001;909(1-2):187-193.
Bjarkam CR, Nielsen MS, Glud AN, et al. Neuromodulation in a minipig MPTP model of Parkinson disease. Br J Neurosurg 2008;22(Suppl 1):S9-S12.
Hu X, Zhang D, Pang H, et al. Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. J Immunol 2008;181(10):7194-7204.
Chen C, Turnbull DM, Reeve AK. Mitochondrial dysfunction in Parkinson's disease-cause or consequence? Biology 2019;8(2):38.
Chen C, McDonald D, Blain A, et al. Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson's disease. NPJ Parkinsons Dis 2021;7(1):39.
Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006;38(5):518-520.
Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006;38(5):515-517.
Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 2008;283(14):9089-9100.
Ludtmann MHR, Angelova PR, Horrocks MH, et al. α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease. Nat Commun 2018;9(1):2293.
McAvoy K, Kawamata H. Glial mitochondrial function and dysfunction in health and neurodegeneration. Mol Cell Neurosci 2019;101:103417.
Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011;14(6):724-738.
Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol 2006;209(Pt 12):2304-2311.
Bolaños JP. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J Neurochem 2016;139:115-125.
Proia P, Di Liegro CM, Schiera G, Fricano A, Di Liegro I. Lactate as a metabolite and a regulator in the central nervous system. Int J Mol Sci 2016;17(9):1450.
Russell OM, Gorman GS, Lightowlers RN, Turnbull DM. Mitochondrial diseases: hope for the future. Cell 2020;181(1):168-188.
Fiebig C, Keiner S, Ebert B, et al. Mitochondrial dysfunction in astrocytes impairs the generation of reactive astrocytes and enhances neuronal cell death in the cortex upon photothrombotic lesion. Front Mol Neurosci 2019;12:40.
Chang Q, Ornatsky O, Hedley D. Staining of frozen and formalin-fixed, paraffin-embedded tissues with metal-labeled antibodies for imaging mass cytometry analysis. Curr Protoc Cytom 2017;82:12.47.11-12.47.18.
Warren C, McDonald D, Capaldi R, et al. Decoding mitochondrial heterogeneity in single muscle fibres by imaging mass cytometry. Sci Rep 2020;10(1):15336.
Bankhead P, Loughrey MB, Fernandez JA, et al. QuPath: open source software for digital pathology image analysis. Sci Rep 2017;7(1):16878.
Team RC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2020.
Rocha MC, Grady JP, Grunewald A, et al. A novel immunofluorescent assay to investigate oxidative phosphorylation deficiency in mitochondrial myopathy: understanding mechanisms and improving diagnosis. Sci Rep 2015;5:15037.
Oberg AL, Mahoney DW. Linear mixed effects models. Methods Mol Biol 2007;404:213-234.
James G, Witten D, Hastie T, Tibshirani R. An Introduction to Statistical Learning. New York, USA: Springer; 2013.
Ben Haim L, Carrillo-de Sauvage MA, Ceyzeriat K, Escartin C. Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 2015;9:278.
Kruschke JK. Bayesian estimation supersedes the t test. J Exp Psychol Gen 2013;142(2):573-603.
Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 2017;18(2):101-113.
Bantle CM, Hirst WD, Weihofen A, Shlevkov E. Mitochondrial dysfunction in astrocytes: a role in Parkinson's disease? Front Cell Dev Biol 2021;8:608026.
Lovatt D, Sonnewald U, Waagepetersen HS, et al. The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 2007;27(45):12255-12266.
Davis CH, Kim KY, Bushong EA, et al. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A 2014;111(26):9633-9638.
Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 2016;535(7613):551-555.