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Neurotoxic conversion of beta-synuclein: a novel approach to generate a transgenic mouse model of synucleinopathies?
- Source :
- Journal of neurology. 256
- Publication Year :
- 2009
-
Abstract
- Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as alpha-syn deposits, compromised function of dopaminergic neurons, fibrillization of alpha-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of alpha-syn tg mice may be required. We predict that beta-synuclein (beta-syn), the homologue of alpha-syn, might be a key molecule for this purpose. Although beta-syn is a neuroprotective molecule counteracting the alpha-syn pathology in tg mice, it was previously shown that both beta-syn and gamma-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson's disease and DLB. Furthermore, two missense mutations (P123H and V70M) of beta-syn were recently identified in DLB. These mutants of beta-syn were prone to aggregate in vitro and overexpression of these mutant beta-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of beta-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant beta-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional alpha-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant beta-syn/alpha-syn might be characterized by a more accelerated phenotype of synucleinopathies.
- Subjects :
- Genetically modified mouse
Lewy Body Disease
Parkinson's disease
animal diseases
Transgene
Mutation, Missense
Context (language use)
Biology
Mice
beta-Synuclein
medicine
Animals
Humans
heterocyclic compounds
Genetic Predisposition to Disease
Synucleinopathies
Dementia with Lewy bodies
Neurodegeneration
Brain
Parkinson Disease
medicine.disease
nervous system diseases
Cell biology
Astrogliosis
Disease Models, Animal
nervous system
Neurology
health occupations
alpha-Synuclein
Lewy Bodies
Neurology (clinical)
Neuroscience
Subjects
Details
- ISSN :
- 14321459
- Volume :
- 256
- Database :
- OpenAIRE
- Journal :
- Journal of neurology
- Accession number :
- edsair.doi.dedup.....a0de9d30182b26a2ec05ea021465c677