These transgenic mice, sometimes referred to as hm2α-SYN-39, contain a mutated human alpha synuclein protein found in human Parkinson Disease patients and under the control of the rat tyrosine hydroxylase promoter. Expression is detected in cell bodies, axons, and terminals of the nigrostriatal system.
Eric Richfield, Rutger's University (EOHSI/UMDNJ)
These hm2α-SYN-39 mice express a doubly-mutant form of human alpha-synuclein (hα-SYN) containing the A30P and A53T human mutations associated with autosomal dominant Parkinson's disease, under the control of the rat tyrosine hydroxylase promoter. Expression of hα-SYN is detected in cell bodies, axons, and terminals of the nigrostriatal system (mRNA expression in midbrain, eye, and adrenal gland, with high levels of protein expression in the cell bodies of dopaminergic neurons in the midbrain and striatum). Hemizygous mice exhibit several Parkinson's disease-related characteristics including increased density of the dopamine transporter, impairments of the ubiquitin-proteasome system, and age-related progressive loss of locomotor activity and substantia nigra pars compacta dopaminergic neurons. The Parkinson's disease-related phenotype of hm2α-SYN-39 mice is more severe than that of the control strain (hwα-SYN-5, see Stock No. 008245). These hm2α-SYN-39 transgenic mice may be useful for studying Parkinson's disease, Lewy bodies, neurodegeneration, and synaptic plasticity.
A 469 bp human alpha-synuclein cDNA was modified by site-directed mutagenesis to contain the A30P and A53T Parkinson's disease-linked mutations. This mutant cDNA was and then placed downstream of a 9 kb rat tyrosine hydroxylase promoter (and splice donor/intron/splice acceptor) and upstream of a polyA signal. The resulting transgene was injected into C57BL/6 oocytes. Mice from founder line 39 (hm2α-SYN-39) were found to have the highest levels of transgene mRNA expression in midbrain. These hm2α-SYN-39 mice were maintained by breeding transgenic mice with wildtype or C57BL/6J for many generations prior sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.
|Expressed Gene||SNCA, synuclein alpha, human|
|Site of Expression|
|Allele Name||transgene insertion 39, Eric K Richfield|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||THsynDM; Tg(Th-SNCA*A30P*A53T)39Fed; Tg(Thy1-SNCA*A30P,A53T)39Fed; hm2alpha-SYN-39|
|Gene Symbol and Name||Tg(Th-SNCA*A30P*A53T)39Eric, transgene insertion 39, Eric K Richfield|
|Gene Synonym(s)||THsynDM; Tg(Th-SNCA*A30P*A53T)39Fed; Tg(Th-SNCA*A30P*A53T)39Fed; Tg(Thy1-SNCA*A30P*A53T)39Fed; Tg(Thy1-SNCA*A30P,A53T)39Fed; Tg(Thy1-SNCA*A30P,A53T)39Fed; hm2alpha-SYN-39; transgene insertion 39, Howard J Federoff|
|Promoter||Th, tyrosine hydroxylase, rat|
|Expressed Gene||SNCA, synuclein alpha, human|
|Strain of Origin||C57BL/6|
|General Note||Young transgenic mice demonstrated significantly increased locomotor activity and a shorter time to right compared to both nontransgenic littermates and Tg(SNCA)5Fed transgenic mice, which express the wild-type human gene under control of a 9 kb rat Thy1promoter. Locomotor responses to amphetamine were impaired in young transgenic mice. The abnormal axons visualized in the median forebrain bundle of transgenic mice were more dilated and beaded in appearance compared to those seen in nontransgenic littermate controls. The terminals in the nucleus accumbens of transgenic mice also appeared abnormal with the smaller caliber processes and terminals often dilated or enlarged compared to those seen in nontransgenic littermate controls. Neither compact round cytoplasmic inclusions nor intranuclear inclusions were identified in transgenic mice at 4 months of age. J). Axons in transgenic mice that stained for Thy1 were beaded and dilated in appearance and displayed increased discontinuities.|
|Molecular Note||The transgene contains a 9 kb rat tyrosine hydroxylase promoter, a splice donor/intron/splice acceptor, a poly(A) site from the human growth hormone gene, and a mutated human alpha synuclein cDNA encoding a protein that carries two amino acid substitutions, Ala53Thr and Ala30Pro, which are found in human Parkinson Disease patients. RT-PCR detected transgene expression in midbrain, eye, and adrenal gland. Real time quantitative RT-PCR as well as in situ hybridization histochemistry detected high levels of transgene expression in the midbrain. Catecholaminergic nuclei in the brain of transgenic mice expressed both human mRNA and human protein. These mice express high levels of the human protein in the cell bodies of dopaminergic neurons in the midbrain and its main projection region, the striatum, dopaminergic dendrites, and nigrostriatal axons and terminals.|
|Mutations Made By|| |
Eric Richfield, Rutger's University (EOHSI/UMDNJ)
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