Mutations: SNCA A30P, SNCA A53T
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J
Genetic Background: Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J.
Availability: Available through The Jackson Laboratory, Stock# 008239, Live.
This transgenic mouse model of Parkinson’s disease, called the HM2 model, expresses mutant human α-synuclein in dopaminergic neurons. Hemizygous mice exhibit age-related abnormalities in the dopaminergic system, including low dopamine levels and difficulties with motor coordination (Richfield et al., 2002).
The tyrosine hydroxylase (TH) promoter drives transgene expression in this model, directing expression to dopaminergic neurons. Human α-synuclein was detected in TH-positive cells in substantia nigra, ventral tegmental area, and the locus coeruleus. Human α-synuclein protein was also found in terminal projections in the striatum, nucleus accumbens, olfactory tubule, and cerebral cortex. The amount of transgenic protein in hemizygous mice is approximately half of endogenous mouse protein.
These transgenic mice progressively lose dopaminergic neurons in the substantia nigra pars compacta (19 percent by 8.5 months and 55 percent by 19 months) (Thiruchelvam et al., 2004), and develop morphological abnormalities within the dopaminergic system (Richfield et al., 2002). For example, axons in the median forebrain bundle appear dilated and have a punctate, “beaded” appearance compared to axons in non-transgenic littermates.
Mutant human α-synuclein was detected in dopaminergic neurons, both cytoplasmic and nuclear. Lewy body-like inclusions are not observed in this model, at least by four months of age.
Compared with non-transgenic littermates, HM2 mice exhibit an age-dependent decrease in striatal dopamine and its primary metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenyl-acetic acid (DOPAC). Measurements of all three substances were lower in HM2 mice than controls at advanced ages (13–23 months).
Behaviorally, HM2 mice showed several motor abnormalities. As young adults (two to three months), they were more active than non-transgenic littermates as measured by spontaneous locomotor activity. However, by middle age (seven to nine months), they were significantly less active, and this difference was even greater in old age (13–23 months). In addition, old HM2 mice took significantly more time to right themselves from an inverted screen, indicating an age-dependent decrease in motor coordination. However, no deficiencies in Rotarod performance, grip strength, or open-field movements were detected at six months of age (Yan et al., 2017).
The behavior of HM2 mice also differed from controls when challenged with repeated administration of amphetamine. Specifically, HM2 mice showed less increase in locomotor activity than non-transgenic mice upon second exposure to the drug.
Proteasome dysfunction has been reported in aged transgenic mice (Chen et al., 2006), and proteomic profiling revealed several alterations in protein expression in the substantia nigra of six-month-old mice (Yan et al., 2017). In particular, the NAD+-dependent protein deacetylase sirtuin 1 was reduced approximately fourfold in the substantia nigra pars compacta of 12-month-old transgenic mice, possibly due to alterations in the ubiquitin-proteasome system (Zhang et al., 2018).
This model expresses a transgene encoding human α-synuclein with two mutations (A30P and A53T) driven by 9kb rat tyrosine hydroxylase (TH) promoter.
hm2αSYN-39 -B6JOla - congenic background (Prasad et al., 2011).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- α-synuclein Inclusions
- Non-Motor Impairment
- Mitochondrial Abnormalities
Progressive loss of dopaminergic neurons was reported in the substantia nigra pars compacta (19 percent reduction at 8.5 months and 55 percent at 19 months).
Striatal dopamine concentrations were lower at all ages tested, including the earliest age, 2-3 months. Dopamine concentrations dropped with age, and levels of metabolites (e.g., DOPAC and HVA) were also lower in HM2 mice than non-Tg by 13-23 months of age.
Inclusions were not observed at any age. Diffuse α- synuclein protein was both cytoplasmic and nuclear.
At young age 2-3 months, HM2 mice were more active than non-Tg controls, but by middle age (7-9 months) they were less active. At advanced ages (13-23 months), they also exhibited impaired coordination as measured by the time it took to right themselves from an inverted wire screen. However, no deficiencies in Rotarod performance, grip strength, or open-field movements were detected at 6 months.
Last Updated: 07 Feb 2019
- Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol. 2002 May;175(1):35-48. PubMed.
- Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK. Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur J Neurosci. 2004 Feb;19(4):845-54. PubMed.
- Yan J, Zhang P, Jiao F, Wang Q, He F, Zhang Q, Zhang Z, Lv Z, Peng X, Cai H, Tian B. Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l. PLoS One. 2017;12(8):e0182092. Epub 2017 Aug 3 PubMed.
- Chen L, Thiruchelvam MJ, Madura K, Richfield EK. Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol Dis. 2006 Jul;23(1):120-6. Epub 2006 May 19 PubMed.
- Zhang Q, Zhang P, Qi GJ, Zhang Z, He F, Lv ZX, Peng X, Cai HW, Li TX, Wang XM, Tian B. Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models. Biochim Biophys Acta Gen Subj. 2018 Jun;1862(6):1443-1451. Epub 2018 Mar 21 PubMed.
- Prasad K, Tarasewicz E, Strickland PA, O'Neill M, Mitchell SN, Merchant K, Tep S, Hilton K, Datwani A, Buttini M, Mueller-Steiner S, Richfield EK. Biochemical and morphological consequences of human α-synuclein expression in a mouse α-synuclein null background. Eur J Neurosci. 2011 Feb;33(4):642-56. PubMed.
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