The A30P α-synuclein mutation decreases subventricular zone proliferation.

Animals Calbindin 2 / metabolism Cell Death Cell Proliferation Disease Models, Animal Dopamine / metabolism Humans Interneurons / cytology Lateral Ventricles / cytology Mice Mice, Inbred C57BL Mice, Transgenic Neurogenesis / genetics Olfactory Bulb / cytology Parkinson Disease / genetics Point Mutation Tyrosine 3-Monooxygenase / metabolism alpha-Synuclein / genetics

Journal

Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958

Informations de publication

Date de publication:
15 07 2019
Historique:
received: 21 12 2018
revised: 05 03 2019
accepted: 14 03 2019
entrez: 4 7 2019
pubmed: 4 7 2019
medline: 13 3 2020
Statut: ppublish

Résumé

Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P SNCA familial PD point mutation on an Snca-/- background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca-/- and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca-/- mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca-/-, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca-/- mice. Cell death decreased in the OB granule layer of Snca-/- and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca-/- and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.

Identifiants

DOI: 10.1093/hmg/ddz057 PMID: 31267130 PMC: PMC6606853
pubmed: 31267130
pii: 5389928
doi: 10.1093/hmg/ddz057
pmc: PMC6606853
doi:

Substances chimiques

Calbindin 2 0
SNCA protein, human 0
alpha-Synuclein 0
Tyrosine 3-Monooxygenase EC 1.14.16.2
Dopamine VTD58H1Z2X

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2283-2294

Subventions

Organisme : Parkinson's UK
ID : H-1301
Pays : United Kingdom
Organisme : Parkinson's UK
ID : J-0901
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom

Informations de copyright

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Auteurs

Xue-Ming Zhang (XM)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.
College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China.

Sabina Anwar (S)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford, UK.

Yongsoo Kim (Y)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.

Jennifer Brown (J)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.

Isabelle Comte (I)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.

Huan Cai (H)

College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China.

Ning-Ning Cai (NN)

College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China.

Richard Wade-Martins (R)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford, UK.

Francis G Szele (FG)

Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Protéines de liaison au calcium › Calbindines › Calbindine-2 › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Catéchols › Catécholamines › Dopamine › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Cellules › Neurones › Interneurones › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Ventricules cérébraux › Ventricules latéraux › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › The A30P α-synuclein mutation decreases...
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questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Neurogenèse › The A30P α-synuclein mutation decreases...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Bulbe olfactif › The A30P α-synuclein mutation decreases...
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questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › alpha-Synucléine › The A30P α-synuclein mutation decreases...