Species: Mouse
Genes: SNCA
Modification: SNCA: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: N/A
Genetic Background: Inbred 129/SvEvTac background.
Availability: Unknown.

Summary
These mice were generated by partially deleting the Snca gene (Cabin et al., 2002). Homozygous knockout (KO) mice are viable and appear to live a normal lifespan. Alpha-synuclein RNA and protein were undetectable in homozygous α-synuclein KO mice. They have no gross morphological or behavioral abnormalities, however, they do exhibit abnormalities in synaptic morphology and function, along with fairly subtle behavioral changes. Over the years, these KO mice have been bred to a variety of other mouse lines, including those expressing human α-synuclein, such as PAC-Tg(SNCAWT) and PAC-Tg(SNCAA53T), MitoPark mice with disrupted mitochondria, and Tg2576 mice overexpressing human APP (Ekstrand et el., 2007; Kallhoff et al., 2007; Vinueza-Gavilanes et al., 2013).

Neuropathology
The brains of α-synuclein KO mice appear largely normal. No significant differences were observed with unbiased stereology in the number of tyrosine hydroxylase–positive neurons in the midbrain between KO and wild-type control mice at 11 or 18 months of age (Kuo et al., 2010). However, electron microscopy (EM) showed a reduced number of synaptic vesicles in hippocampal neurons (Cabin et al., 2002). Notably, the reserve pool was about 50 percent smaller in KO neurons compared with wild-type. There were no differences in levels of a battery of synaptic proteins including synapsin, synaptophysin, and SNAP-25.

In an electrophysiological assay involving stimulation of Schaffer collaterals, basal synaptic transmission in α-synuclein KO mice was intact (Cabin et al, 2002). Similarly, there was no difference in paired pulse facilitation (PPF), a form of short-term hippocampal plasticity, compared with wild-type mice. Also, paired-pulse experiments in the corticostriatal pathway showed no difference between KO and wild-type mice, but notably, both groups exhibited depression rather than facilitation in this region (Watson et al., 2009). KO mice also had a similar response to a high-frequency stimulation, suggesting a comparable number of docked vesicles (Cabin et al., 2002). However, consistent with EM data, the response to prolonged repetitive stimulation indicated a smaller reserve pool of synaptic vesicles in KO mice. Impaired replenishment of the readily releasable pool of vesicles led to more pronounced synaptic depression in KO neurons.

Additional studies have reinforced evidence of disrupted synaptic function. In particular, glutamate release, as measured in forebrain synaptoneurosomes, was impaired in KO versus wild-type mice (Sarafian et al., 2017). Moreover, protein level of complexin 1, which is involved in vesicle release, was upregulated in the midbrain/brainstem of 3-month-old KO mice versus wild-type mice (Gispert et al., 2015).

Dopamine abnormalities
Levels of striatal dopamine and its metabolites did not significantly differ across groups in an experiment comparing KO mice, wild-type controls, and mice overexpressing wild-type or mutant (A53T) human α-synuclein (Kuo et al., 2010). However, this study may have lacked sufficient statistical power to detect subtle differences, as numerical variations were noted between KO and wild-type mice. Consistent with this possibility, a separate study focused specifically on the comparison of KO and wild-type mice found significantly reduced striatal dopamine levels in KO mice at both young (6 months) and old (18 months or older) ages (Kurz et al., 2010).

Motor behavior
Behaviorally, α-synuclein KO mice appear largely normal. They display normal reflexes and sensory abilities (Cabin et al., 2002). They performed similarly to controls in most assays of motor function (e.g., Rotarod, distance travelled in open-field test); however, they reared on hind legs less frequently than wild-type controls. They also spent less time in the center of the field, indicating a possible anxiety-like phenotype. Similar performance to control mice on the Rotarod (latency to fall) and open-field test (locomotor activity) were confirmed in another report in mice aged 6, 12, and 18 months (Kuo et al., 2010).

There were no differences between α-synuclein KO mice and wild-type controls in terms of amphetamine-induced locomotor activity (Cabin et al., 2002).

Non-motor behavior
Learning and memory appears intact in α-synuclein KO mice. At 6 to 10 months of age, α-synuclein KO mice performed as well as wild-type controls on the Morris water maze, suggesting normal spatial memory (Cabin et al., 2002). Likewise, contextual memory was intact as measured by their freezing response in tests of conditioned fear.

Olfactory function does not appear to be affected in KO mice, based on the novel odorant test at 12 months of age and the buried Froot loop test at 12 and 18 months of age (Kuo et al., 2010).

In neonatal KO mice aged 7 days, isolation-induced ultrasonic vocalizations were observed at a greater frequency than in wild-type mice, which can be a sign of anxiety-like behavior (Kurz et al., 2010).

Neuroinflammation
Microglia cultured from α-synuclein KO brains exhibit distinct morphology and functionality compared to wild-type microglia (Austin et al., 2006). Notably, KO microglia have a more reactive phenotype (i.e., more ramified). They also have more vacuole-like structures. They exhibit a heightened response to lipopolysaccharide stimulation and secrete elevated levels of proinflammatory cytokines, such as TNF-α and interleukin-6. In culture, their phagocytic ability is impaired.

Mitochondrial Abnormalities
Snca deletion impacted lipid composition of the brain. Alpha-synuclein KO mice had reduced levels of the mitochondrial phospholipid cardiolipin and also reduced levels of phosphatidylglycerol (Ellis et al., 2005; Barceló-Coblijn et al., 2007). The amount of mitochondrial DNA relative to the amount of nuclear DNA did not differ between KO and wild-type brains, suggesting comparable amounts of mitochondria. However, evidence of mitochondrial abnormalities were observed in the form of reduced activity of complex I/III of the electron transport chain (Ellis et al., 2005).

Other Phenotypes
No notable differences in colonic motility or whole-gut transit time were observed between KO mice and wild-type controls at 3, 6, 12, or 18 months of age (Kuo et al., 2010). However, KO mice had a lower gut-vascular permeability than wild-type mice (Yang et al., 2024).

Glucocerebrosidase, a lysosomal enzyme involved in breaking down the lipid glucosylceramide, exhibited elevated activity in KO mice compared to wild-type mice, despite unchanged protein levels (Fishbein et al., 2014). Brain lipid metabolism in other pathways was also altered in KO mice, including decreased incorporation of arachidonic acid (20:4n-6) into phospholipids (Golovko et al., 2006), further supporting the mitochondrial lipid abnormalities described above.

In the striatum of KO mice, mRNA analysis revealed no differences from wild-type levels in the expression of Parkinson’s disease–related genes, including Lrrk2 (leucine-rich repeat kinase 2), Uch-L1 (ubiquitin C-terminal hydrolase-L1), DJ-1, and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) (Westerlund et al., 2008).

In a microarray analysis of striatal and cerebellar tissue of 6- and 21-month-old KO mice, 12 genes were found to be altered, including a robust decrease in Foxp1, a transcription factor involved in neural connectivity and sound control (Kurz et al., 2010). Decreases in Foxp1 were also observed in the brainstem and midbrain via quantitative PCR. Protein and mRNA expression of glyoxalase I (GLO1), which is involved in the glucose stress response, was found to be induced in the striatum of KO mice (Kurz et al., 2011). Correspondingly, there was an increase in glucose stress markers in the brains of KO mice, including fructosyl-lysine.

KO mice are more susceptible to high-fat diet–induced insulin resistance and demonstrate altered glucose regulation and homeostasis in response (Rodriguez-Araujo et al., 2015).

Alpha-synuclein KO mice also exhibit defects in detoxification of certain chemicals. Specifically, compared to wild-type mice, KO mice experience robust and prolonged methemoglobinemia—a condition where hemoglobin in red blood cells loses its ability to carry oxygen—after exposure to para-aminopropiophenone or its active metabolite (Kuo and Nussbaum, 2015). This suggests that α-synuclein may serve a protective function against chemical-induced toxicity.

Modification Details
The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene (Cabin et al., 2002).

Related Strains

α-synuclein A53T (Tg) on SNCA KO - PAC-Tg(SNCAA53T), JAX# 010799
α-synuclein A30P (Tg) on SNCA KO - JAX# 010788
α-synuclein wild-type (Tg) on SNCA KO - JAX# 010710

Phenotype Characterization

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References

Research Models Citations

1. α-synuclein A53T Mouse (Tg) on SNCA KO
2. Tg2576

Paper Citations

1. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 2002 Oct 15;22(20):8797-807. PubMed.
2. Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson FS, Trifunovic A, Hoffer B, Cullheim S, Mohammed AH, Olson L, Larsson NG. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30. PubMed.
3. Kallhoff V, Peethumnongsin E, Zheng H. Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease. Mol Neurodegener. 2007 Mar 16;2:6. PubMed.
4. Vinueza-Gavilanes R, Bravo-González JJ, Basurco L, Boncristiani C, Fernández-Irigoyen J, Santamaría E, Marcilla I, Pérez-Mediavilla A, Luquin MR, Vales A, González-Aseguinolaza G, Aymerich MS, Aragón T, Arrasate M. Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models. Neurobiol Dis. 2023 Jul;183:106166. Epub 2023 May 26 PubMed.
5. Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet. 2010 May 1;19(9):1633-50. Epub 2010 Jan 27 PubMed.
6. Watson JB, Hatami A, David H, Masliah E, Roberts K, Evans CE, Levine MS. Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein. Neuroscience. 2009 Mar 17;159(2):501-13. PubMed.
7. Sarafian TA, Littlejohn K, Yuan S, Fernandez C, Cilluffo M, Koo BK, Whitelegge JP, Watson JB. Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated α-synuclein. J Neurosci Res. 2017 Sep;95(9):1871-1887. Epub 2017 Jan 24 PubMed.
8. Gispert S, Kurz A, Brehm N, Rau K, Walter M, Riess O, Auburger G. Complexin-1 and Foxp1 Expression Changes Are Novel Brain Effects of Alpha-Synuclein Pathology. Mol Neurobiol. 2015 Aug;52(1):57-63. Epub 2014 Aug 12 PubMed.
9. Kurz A, Double KL, Lastres-Becker I, Tozzi A, Tantucci M, Bockhart V, Bonin M, García-Arencibia M, Nuber S, Schlaudraff F, Liss B, Fernández-Ruiz J, Gerlach M, Wüllner U, Lüddens H, Calabresi P, Auburger G, Gispert S. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice. PLoS One. 2010 Jul 7;5(7):e11464. PubMed.
10. Austin SA, Floden AM, Murphy EJ, Combs CK. Alpha-synuclein expression modulates microglial activation phenotype. J Neurosci. 2006 Oct 11;26(41):10558-63. PubMed.
11. Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barceló-Coblijn GC, Nussbaum RL. Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol. 2005 Nov;25(22):10190-201. PubMed.
12. Barceló-Coblijn G, Golovko MY, Weinhofer I, Berger J, Murphy EJ. Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice. J Neurochem. 2007 Apr;101(1):132-41. Epub 2007 Jan 23 PubMed.
13. Yang Y, Stewart T, Zhang C, Wang P, Xu Z, Jin J, Huang Y, Liu Z, Lan G, Liang X, Sheng L, Shi M, Cai Z, Zhang J. Erythrocytic α-Synuclein and the Gut Microbiome: Kindling of the Gut-Brain Axis in Parkinson's Disease. Mov Disord. 2024 Jan;39(1):40-52. Epub 2023 Oct 5 PubMed.
14. Fishbein I, Kuo YM, Giasson BI, Nussbaum RL. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation. Brain. 2014 Dec;137(Pt 12):3235-47. Epub 2014 Oct 27 PubMed.
15. Golovko MY, Rosenberger TA, Faergeman NJ, Feddersen S, Cole NB, Pribill I, Berger J, Nussbaum RL, Murphy EJ. Acyl-CoA synthetase activity links wild-type but not mutant alpha-synuclein to brain arachidonate metabolism. Biochemistry. 2006 Jun 6;45(22):6956-66. PubMed.
16. Westerlund M, Ran C, Borgkvist A, Sterky FH, Lindqvist E, Lundströmer K, Pernold K, Brené S, Kallunki P, Fisone G, Olson L, Galter D. Lrrk2 and alpha-synuclein are co-regulated in rodent striatum. Mol Cell Neurosci. 2008 Dec;39(4):586-91. Epub 2008 Aug 27 PubMed.
17. Kurz A, Rabbani N, Walter M, Bonin M, Thornalley P, Auburger G, Gispert S. Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress. Cell Mol Life Sci. 2011 Feb;68(4):721-33. Epub 2010 Aug 14 PubMed.
18. Rodriguez-Araujo G, Nakagami H, Takami Y, Katsuya T, Akasaka H, Saitoh S, Shimamoto K, Morishita R, Rakugi H, Kaneda Y. Low alpha-synuclein levels in the blood are associated with insulin resistance. Sci Rep. 2015 Jul 10;5:12081. PubMed.
19. Kuo YM, Nussbaum RL. Prolongation of Chemically-Induced Methemoglobinemia in Mice Lacking α-synuclein: A Novel Pharmacologic and Toxicologic Phenotype. Toxicol Rep. 2015;2:504-511. PubMed.

Further Reading