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Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice.
- Source :
-
Brain structure & function [Brain Struct Funct] 2018 Apr; Vol. 223 (3), pp. 1357-1368. Date of Electronic Publication: 2017 Nov 09. - Publication Year :
- 2018
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Abstract
- In the adult mammalian hippocampus, new neurons are constantly added to the dentate gyrus. Adult neurogenesis is impaired in several neurodegenerative mouse models including α-synuclein (a-syn) transgenic mice. Among different a-syn species, a-syn oligomers were reported to be the most toxic species for neurons. Here, we studied the impact of wild-type vs. oligomer-prone a-syn on neurogenesis. We compared the wild-type a-syn transgenic mouse model (Thy1-WTS) to its equivalent transgenic for oligomer-prone E57K-mutant a-syn (Thy1-E57K). Transgenic a-syn was highly expressed within the hippocampus of both models, but was not present within adult neural stem cells and neuroblasts. Proliferation and survival of newly generated neurons were unchanged in both transgenic models. Thy1-WTS showed a minor integration deficit regarding mushroom spine density of newborn neurons, whereas Thy1-E57K exhibited a severe reduction of all spines. We conclude that cell-extrinsic a-syn impairs mushroom spine formation of adult newborn neurons and that oligomer-prone a-syn exacerbates this integration deficit. Moreover, our data suggest that a-syn reduces the survival of newborn neurons by a cell-intrinsic mechanism during the early neuroblast development. The finding of increased spine pathology in Thy1-E57K is a new pathogenic function of oligomeric a-syn and precedes overt neurodegeneration. Thus, it may constitute a readout for therapeutic approaches.
- Subjects :
- Animals
Bromodeoxyuridine metabolism
Caspase 3 metabolism
Cell Proliferation genetics
Disease Models, Animal
Doublecortin Domain Proteins
Gene Expression Regulation genetics
Glutamic Acid genetics
Lysine genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microtubule-Associated Proteins metabolism
Neurons pathology
Neurons ultrastructure
Neuropeptides metabolism
Phosphopyruvate Hydratase metabolism
SOXB1 Transcription Factors metabolism
Hippocampus pathology
Mutation genetics
Neurodegenerative Diseases genetics
Neurodegenerative Diseases pathology
Neurogenesis genetics
alpha-Synuclein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1863-2661
- Volume :
- 223
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Brain structure & function
- Publication Type :
- Academic Journal
- Accession number :
- 29124353
- Full Text :
- https://doi.org/10.1007/s00429-017-1561-5