Adaptive acetylcholinesterase splicing patterns attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice.
Eur J Neurosci
; 23(11): 2915-22, 2006 Jun.
Article
em En
| MEDLINE
| ID: mdl-16819980
ABSTRACT
Balanced dopaminergic cholinergic interactions are crucial for proper basal ganglia function. This is dramatically demonstrated by the worsening of Parkinson's disease symptoms following acetylcholinesterase (AChE) inhibition. Typically, in the brain, the synapse-anchored synaptic AChE (AChE-S) variant is prevalent whereas the soluble readthrough AChE (AChE-R) variant is induced in response to cholinesterase inhibition or stress. Because of the known functional differences between these variants and the fact that AChE-R expression is triggered by various stimuli that themselves are often associated with Parkinson's disease risk, we hypothesized that the splice shift to AChE-R plays a functional role in Parkinsonian progression. After establishing that Paraoxon-induced AChE inhibition indeed aggravates experimental Parkinsonism triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, we tested the roles of individual AChE variants by exposing transgenic mice overexpressing either the AChE-S or AChE-R variant to MPTP. Differential reductions of tyrosine hydroxylase levels in the striatum and substantia nigra indicated that transgenic AChE-R expression confers resistance as compared with the parent FVB/N strain. In contrast, AChE-S overexpression accelerated the MPTP-induced damage. Survival, behavioral measures and plasma corticosterone levels were also compatible with the extent of the dopaminergic damage. Our findings highlight the functional differences between individual AChE variants and indicate that a naturally occurring stress or AChE inhibitor-induced splicing shift can act to minimize dopaminergic cholinergic imbalances. We propose that inherited or acquired alternative splicing deficits could accelerate Parkinsonism and that, correspondingly, adaptive alternative splicing events may attenuate disease progression.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetilcolinesterase
/
Splicing de RNA
/
Intoxicação por MPTP
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Eur J Neurosci
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Israel