Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism

Simple item page
dc.contributor.authorMerino Galán, Leyre
dc.contributor.authorJiménez Urbieta, Haritz
dc.contributor.authorZamarbide, Marta
dc.contributor.authorRodríguez Chinchilla, Tatiana
dc.contributor.authorBelloso Iguerategui, Arantzazu
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorAiastui, Ana
dc.contributor.authorDoudnikoff, Evelyne.
dc.contributor.authorBézard, Erwan
dc.contributor.authorOuro, Alberto
dc.contributor.authorKnafo, Shira
dc.contributor.authorGago, Belén
dc.contributor.authorQuiroga Varela, Ana
dc.contributor.authorRodríguez Oroz, María Cruz
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2023-01-18T11:17:19Z
dc.date.available2023-01-18T11:17:19Z
dc.date.issued2022
dc.date.updated2023-01-18T10:43:16Z
dc.description.abstractSynaptic impairment might precede neuronal degeneration in Parkinson’s disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. Sequential window acquisition of all theoretical mass spectra proteomics identified deregulated proteins involved first in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics was followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres was evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolved. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated postsynaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells to delay or prevent the development of Parkinson’s disease.en
dc.description.sponsorshipThis study was funded by the Instituto de Salud Carlos III through the projects PI14/00763 and PI19/01915 (co-funded by ERDF/ESF, ‘Investing in your future’). L.M.-G. held a Predoctoral Research Fellowship from the University of the Basque Country (UPV/EHU). T.R.-C. and A.Q.-V. were funded by CIBERNED. T.R.-C. held a Fundación Jesús de Gangoiti Barrera Foundation grant (Bilbao, Spain). H.J.-U. and A.B.-I. held a Predoctoral Research Fellowship from the Government of the Basque Country. Israel Science Foundation (536/19) and the Spanish Ministry of Science (SAF2016-78071-R) funded the contribution of S.K. and A.O.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMerino-Galán, L., Jimenez-Urbieta, H., Zamarbide, M., Rodríguez-Chinchilla, T., Belloso-Iguerategui, A., Santamaria, E., Fernández-Irigoyen, J., Aiastui, A., Doudnikoff, E., Bézard, E., Ouro, A., Knafo, S., Gago, B., Quiroga-Varela, A., & Rodríguez-Oroz, M. C. (2022). Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism. Brain, 145(6), 2092-2107. https://doi.org/10.1093/brain/awac087en
dc.identifier.doi10.1093/brain/awac087
dc.identifier.issn0006-8950
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/44587
dc.language.isoengen
dc.publisherOxford University Pressen
dc.relation.ispartofBrain 2022: 145; 2092–2107en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/PI14%2F00763/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PI19%2F01915/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement///SAF2016-78071-R/
dc.relation.publisherversionhttps://doi.org/10.1093/brain/awac087
dc.rights© The Author(s) 2022. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondriaen
dc.subjectParkinson's diseaseen
dc.subjectStriatumen
dc.subjectSynapseen
dc.subjectα-synucleinen
dc.titleStriatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonismen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

Files

Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Merino_StriatalSynaptic_1669883757186_42108.pdf
Size:
2.05 MB
Format:
Adobe Portable Document Format
Download
Thumbnail Image
Name:
Merino_StriatalSynaptic_MatCompl_1674038299536.pdf
Size:
1.67 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.78 KB
Format:
Item-specific license agreed to upon submission
Description:
Download

Collections

Artículos de revista DCS - OZS Aldizkari artikuluak
Artículos de revista - Aldizkari artikuluak