C57BL/6-Tg(Th-SNCA*)MI2Mgsp Del(6Snca)1Slab/J

Stock number: 038021
Product name: MI2
Strain synonyms: MI2
Research areas: Neurobiology Research

Description

MI2 mice harbor an α-Syn null allele and a truncated (1-120) human α-synuclein transgene driven by the rat Th promoter. These mice may be useful for studying the pathogenic role of α-synuclein in synucleinopathies, such as Parkinson's Disease.

Detailed description

α-Synuclein is a neuronal protein (coded by Snca) which plays a role in synaptic plasticity and neurotransmitter release. Mutations of Snca have been implicated in a group of neurodegenerative diseases that result from aggregation of α-synuclein in neurons or, in some cases, glial cells. These disorders include Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease (AD), multiple system atrophy, and neurodegeneration with brain iron accumulation. Truncated α-synuclein isoforms are present in patients’ brains and found to be more susceptible to aggregation in the central nervous system. MI2 double mutant mice carry a truncated 1-120 human α-synuclein (SNCA) transgene on a C57BL/6JOlaHsd background; this inbred line has a spontaneous deletion of endogenous α-Syn (DEL(6Snca)1). The MI2 transgene is driven by the rat tyrosine hydroxylase (Th) promoter resulting in expression in noradrenergic and dopaminergic neurons.

Mice that are homozygous for α-Syn null mutation (DEL(6Snca)1) and homozygous for MI2 transgene are viable and fertile. The donating laboratory has indicated that the insertion site of the MI2 transgene has been determined (chromosome 1) but copy number has not been evaluated (February 2023). MI2 double homozygous mice show progressive 1-120 alpha-synuclein aggregation associated with a progressive reduction in striatal dopamine release from the age of 6 months as well as dopaminergic (DA) neuronal death in the substantia nigra starting at 9-12 months of age. The dopamine neuronal cell death is progressive, with 30% reduction of DA neurons by 12 months of age and 50% reduction by 18-20 months of age. These double homozygous MI2 mice also have gait abnormalities, as measured by a forced treadmill system, starting at 6-9 months of age. As well as significant motor impairments, using accelerating rotarod, by 18-20 months of age. These mice may be useful for studying α-synuclein toxicity in Parkinson's Disease.

Development

The MI2 mice carry a truncated human SNCA transgene (1-120) driven by the rat tyrosine hydroxylase promoter (Th) and an α-synuclein null allele (Del(6Snca)1Slab).

C57BL/6JOlaHsd inbred mice are homozygous for a spontaneous 365kb deletion on chromosome 6 (Del(6Snca)1Slab). This deleted region includes the genes coding for α-synuclein (Snca) and multimerin-1 (Mmrn1). These Del(6Snca)1Slab mice, also known as C57BL/6S, were utilized for microinjection of the MI2 transgene construct as noted below.

The (Th-SNCA*)MI2 transgene was generated using truncated (1-120) human α-synuclein cDNA, followed by polyadenylation sequence (PolyA), was subcloned downstream of the rat Th promoter. Purified linearized DNA was microinjected into the pronuclei of fertilized α-Syn null C57Bl/6OlaHsd (Del(6Snca)1Slab) mouse oocytes. Founder line MI2 was established and maintained as a double homozygous colony. The donating laboratory has indicated that the insertion site of the MI2 transgene has been determined (chromosome 1) but copy number has not been evaluated (February 2023).

Frozen sperm, provided by the donating institution, that was homozygous for the α-Syn null mutation (Del(6Snca)1Slab) and homozygous for the (Th-SNCA*)MI2 transgene, was recovered using C57BL/6J (Stock No. 000664) oocytes at The Jackson Laboratory. Subsequently, the recovered line was then cryopreserved by The Jackson Laboratory.

In 2024, a 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. One of the 43 markers throughout the genome was segregating with an unknown source. Also, one of the 5 markers that determine C57BL/6J from C57BL/6N was found to be segregating on Chromosome 19. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Allele

Symbol: Del(6Snca)1Slab
Name: deletion, Chr 6, Schoepfer Lab 1
MGI accession ID: MGI:2154692
Generation method: Spontaneous
Synonyms: alphaS^-; alpha-syn^-; C57BL/6S; Del(6)Snca1Slab; Del1Slab
Marker symbol: Del(6Snca)1Slab
Marker name: deletion, Chr 6, Schoepfer Lab 1
Marker synonyms: Del(6)Snca1Slab; Del1Slab
Chromosome: 6
Strain of origin: C57BL/6JOlaHsd
Molecular note: This chromosomal deletion is 365 kb in length and includes both the Snca gene and the Mmrn1 gene, but not Atoh1 or Atoh2. The deletion was not present in C57BL/6J DNA provided from the Jackson Laboratory, in contrast to C57BL/6JOlaHsd mice from Harlan.

Allele

Symbol: Tg(Th-SNCA*)MI2Mgsp
Name: transgene insertion MI2, Maria Grazia Spillantini
MGI accession ID: MGI:7442149
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: MI2
Marker symbol: Tg(Th-SNCA*)MI2Mgsp
Marker name: transgene insertion MI2, Maria Grazia Spillantini
Chromosome: UN
Strain of origin: C57Bl/6OlaHsd-Del(6Snca)1Slab
Molecular note: The transgenic construct is generated using truncated (1-120) human alpha-synuclein cDNA, followed by polyadenylation sequence (PolyA), and subcloned downstream of the rat Th promoter.