Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting 1–5% of individuals over 60, with a higher incidence in men. It is clinically characterized by progressive motor impairments, including rigidity, bradykinesia, tremors, and gait disturbances. The neuropathological hallmark of...

Full description

Bibliographic Details
Authors: Vaquero Rodríguez, Andrea, Razquin Lizarraga, Jone, Murueta-Goyena Larrañaga, Ane, Miguélez Palomo, Cristina, Ruiz Ortega, José Ángel, Lafuente Sánchez, José Vicente, Bengoetxea Odriozola, Harkaitz, Ortuzar Markes, Naiara
Format: article
Publication Date:2025
Country:España
Institution:Universidad del País Vasco
Repository:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:dnet:addi________::9e36ae8689c645e198af1d823691e8ed
Online Access:http://hdl.handle.net/10810/78641
Access Level:Open access
Keyword:Parkinson's disease
α-synuclein
nigrostriatal pathway
dopaminergic neurons
axonal swellings
microglia
id ES_52ac6ecba57b97a3d416dc6bb689594e
oai_identifier_str oai:dnet:addi________::9e36ae8689c645e198af1d823691e8ed
network_acronym_str ES
network_name_str España
repository_id_str
spelling Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s diseaseVaquero Rodríguez, AndreaRazquin Lizarraga, JoneMurueta-Goyena Larrañaga, AneMiguélez Palomo, CristinaRuiz Ortega, José ÁngelLafuente Sánchez, José VicenteBengoetxea Odriozola, HarkaitzOrtuzar Markes, NaiaraParkinson's diseaseα-synucleinnigrostriatal pathwaydopaminergic neuronsaxonal swellingsmicrogliaParkinson’s disease (PD) is a common neurodegenerative disorder, affecting 1–5% of individuals over 60, with a higher incidence in men. It is clinically characterized by progressive motor impairments, including rigidity, bradykinesia, tremors, and gait disturbances. The neuropathological hallmark of PD is the aggregation of α-synuclein (α-syn) into Lewy bodies (LB) and neurites (LN). Although α-syn plays essential physiological roles, its misfolding and accumulation drive neurodegeneration. In this study, we investigated the temporal progression and anatomical distribution of α-syn pathology using a bilateral adeno-associated virus serotype-9 (AAV9)-mediated α-syn overexpression model in rats. Disease-related features were analyzed at one, two and four months post-injection. Neuronal α-syn overexpression was confirmed as it co-localized predominantly with tyrosine hydroxylase (TH)-positive neurons, distinctly separate from glial markers.Behavioral assessment, immunofluorescence assays, stereological quantification, and optical densitometry revealed progressive motor impairments, dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), and decreased TH + fibers in the striatum and dendrites of the substantia nigra pars reticulata (SNpr). These changes were accompanied by increased microglial activation. Furthermore, axonal swellings in the striatum increased progressively over time, correlating with reductions in striatal TH optical density. By characterizing the temporal dynamics of α-syn-induced pathology, this study underscores the model’s relevance for PD research and highlights critical time windows for evaluating therapeutic interventions.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by a grant PID2021-126434OB-I00 funded by MCIN/AEI/10.13039/501100011033 and ERDF A way of making Europe. It has also been funded by the Basque Government (IT1706-22). This research was conducted in the scope of the Transborder Joint Laboratory (LTC) “non-motor Comorbidities in Parkinson’s Disease (CoMorPD)”. AV-R and JR hold PhD grants from the University of the Basque Country.Springer Nature202620262025info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/78641reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN/PID2021-126434OB-I00/https://link.springer.com/article/10.1007/s00429-025-02959-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/4.0/© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International Licenseoai:dnet:addi________::9e36ae8689c645e198af1d823691e8ed2026-06-18T09:23:17Z
dc.title.none.fl_str_mv Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
title Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
spellingShingle Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
Vaquero Rodríguez, Andrea
Parkinson's disease
α-synuclein
nigrostriatal pathway
dopaminergic neurons
axonal swellings
microglia
title_short Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
title_full Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
title_fullStr Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
title_full_unstemmed Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
title_sort Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease
dc.creator.none.fl_str_mv Vaquero Rodríguez, Andrea
Razquin Lizarraga, Jone
Murueta-Goyena Larrañaga, Ane
Miguélez Palomo, Cristina
Ruiz Ortega, José Ángel
Lafuente Sánchez, José Vicente
Bengoetxea Odriozola, Harkaitz
Ortuzar Markes, Naiara
author Vaquero Rodríguez, Andrea
author_facet Vaquero Rodríguez, Andrea
Razquin Lizarraga, Jone
Murueta-Goyena Larrañaga, Ane
Miguélez Palomo, Cristina
Ruiz Ortega, José Ángel
Lafuente Sánchez, José Vicente
Bengoetxea Odriozola, Harkaitz
Ortuzar Markes, Naiara
author_role author
author2 Razquin Lizarraga, Jone
Murueta-Goyena Larrañaga, Ane
Miguélez Palomo, Cristina
Ruiz Ortega, José Ángel
Lafuente Sánchez, José Vicente
Bengoetxea Odriozola, Harkaitz
Ortuzar Markes, Naiara
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Parkinson's disease
α-synuclein
nigrostriatal pathway
dopaminergic neurons
axonal swellings
microglia
topic Parkinson's disease
α-synuclein
nigrostriatal pathway
dopaminergic neurons
axonal swellings
microglia
description Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting 1–5% of individuals over 60, with a higher incidence in men. It is clinically characterized by progressive motor impairments, including rigidity, bradykinesia, tremors, and gait disturbances. The neuropathological hallmark of PD is the aggregation of α-synuclein (α-syn) into Lewy bodies (LB) and neurites (LN). Although α-syn plays essential physiological roles, its misfolding and accumulation drive neurodegeneration. In this study, we investigated the temporal progression and anatomical distribution of α-syn pathology using a bilateral adeno-associated virus serotype-9 (AAV9)-mediated α-syn overexpression model in rats. Disease-related features were analyzed at one, two and four months post-injection. Neuronal α-syn overexpression was confirmed as it co-localized predominantly with tyrosine hydroxylase (TH)-positive neurons, distinctly separate from glial markers.Behavioral assessment, immunofluorescence assays, stereological quantification, and optical densitometry revealed progressive motor impairments, dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), and decreased TH + fibers in the striatum and dendrites of the substantia nigra pars reticulata (SNpr). These changes were accompanied by increased microglial activation. Furthermore, axonal swellings in the striatum increased progressively over time, correlating with reductions in striatal TH optical density. By characterizing the temporal dynamics of α-syn-induced pathology, this study underscores the model’s relevance for PD research and highlights critical time windows for evaluating therapeutic interventions.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/78641
url http://hdl.handle.net/10810/78641
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN/PID2021-126434OB-I00/
https://link.springer.com/article/10.1007/s00429-025-02959-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408065036484608
score 15,198674

Similar Items