Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model.


Journal

NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390

Informations de publication

Date de publication:
02 Sep 2024
Historique:
received: 17 04 2024
accepted: 05 08 2024
medline: 3 9 2024
pubmed: 3 9 2024
entrez: 2 9 2024
Statut: epublish

Résumé

The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized. We performed a detailed histological study to determine the anatomical distribution of different molecular phenotypes within identified midbrain neurons and their selective vulnerability in control and MPTP-treated monkeys. In the ventral tier of the SNc (nigrosome), neurons rich in Aldh1a1 and Girk2 are intermingled, whereas calbindin is the marker that best identifies the most resilient neurons located in the dorsal tier and ventral tegmental area, recapitulating the well-defined dorsoventral axis of susceptibility to degeneration of dopaminergic neurons. In particular, a loss of Aldh1a1+ neurons in the ventral SNc was observed in parallel to the progressive development of parkinsonism. Aldh1a1+ neurons were the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while Aldh1a1- neurons giving rise to nigropallidal projections remained relatively preserved. Moreover, bundles of entwined Aldh1a1+ dendrites with long trajectories extending towards the substantia nigra pars reticulata emerged from clusters of Aldh1a1+ neurons and colocalized with dense cannabinoid receptor 1 afferent fibers likely representing part of the striatonigral projection that is affected in human disorders, including Parkinson´s disease. In conclusion, vulnerable nigrostriatal-projecting neurons can be identified by using Aldh1a1 and Girk2. Further studies are needed to define the afferent/efferent projection patterns of these most vulnerable neurons.

Identifiants

pubmed: 39223183
doi: 10.1038/s41531-024-00777-0
pii: 10.1038/s41531-024-00777-0
doi:

Types de publication

Journal Article

Langues

eng

Pagination

165

Subventions

Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : CP19/00200
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI23/00672

Informations de copyright

© 2024. The Author(s).

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Auteurs

Natalia López-González Del Rey (NL)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.
PhD Program in Neuroscience Autónoma de Madrid University-Cajal Institute, Madrid, Spain.
Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.

Nagore Hernández-Pinedo (N)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.

Megan Carrillo (M)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.
Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain.

María Del Cerro (M)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.

Noelia Esteban-García (N)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.
PhD Program in Neuroscience Autónoma de Madrid University-Cajal Institute, Madrid, Spain.

Inés Trigo-Damas (I)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.
Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain.
Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Madrid, Spain.

Mariana H G Monje (MHG)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain.
Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

José L Lanciego (JL)

Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain.
CNS Gene Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

Carmen Cavada (C)

PhD Program in Neuroscience Autónoma de Madrid University-Cajal Institute, Madrid, Spain.
Department of Anatomy, Histology and Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain.

José A Obeso (JA)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain. jobeso.hmcinac@hmhospitales.com.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain. jobeso.hmcinac@hmhospitales.com.
Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain. jobeso.hmcinac@hmhospitales.com.

Javier Blesa (J)

HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain. jblesa.hmcinac@hmhospitales.com.
Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain. jblesa.hmcinac@hmhospitales.com.
Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain. jblesa.hmcinac@hmhospitales.com.
Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Madrid, Spain. jblesa.hmcinac@hmhospitales.com.

Classifications MeSH