Influence of Different Promoters on the Expression Pattern of Mutated Human α-Synuclein in Transgenic Mice

Maskri, Lyutha; Zhu, Xin-Ran; Fritzen, Sabrina; Kühn, Kati; Ullmer, Christoph; Engels, Peter; Andriske, Michael; Stichel, Christine C.; Lübbert, Hermann

doi:10.1159/000085064

Cited by 37 publications

(33 citation statements)

References 77 publications

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“…In contrast, CaM_␣-syn1 mice and PrP_␣-syn1 mice showed weaker tg signals, which were limited to the forebrain. This phenomenon corresponds to line-to-line variabilities, caused by copy number and integration site of the tg constructs, which also has been described for permanent (Maskri et al, 2004) and conditional (Mayford et al, 1996) models previously. In both of our responder lines, ␣-syn and ␣-syn1, copy numbers were identical, indicating that position effects attributable to integration of the transgene are responsible for differences in the expression.…”

Section: Discussionsupporting

confidence: 70%

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

165

134

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␣-Synuclein (␣-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether ␣-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type ␣-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting ␣-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, ␣-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.

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Section: Discussionsupporting

confidence: 70%

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

165

134

View full text Add to dashboard Cite

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“…A number of human ␣-synuclein transgenic mouse models have been developed with different promoters (33,38,39,41). These models show varying behavioral phenotypes, neuropathology, and disease duration, depending on the choice of promoters and the magnitude of overexpression (40,(42)(43)(44)(45)(46)(47). In some Thy1 and prion promoter ␣-synuclein Tg mice, the overexpression is about 10-fold higher than normal and is observed throughout the brain, including the cortex, thalamus, and substantia nigra (38 -40).…”

Section: Discussionmentioning

confidence: 99%

Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human α-Synuclein

Zhou¹,

Milder

Freed

2008

Journal of Biological Chemistry

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Abnormal aggregation of human ␣-synuclein in Lewy bodies and Lewy neurites is a pathological hallmark of Parkinson disease and dementia with Lewy bodies. Studies have shown that oxidation and nitration of ␣-synuclein lead to the formation of stable dimers and oligomers through dityrosine cross-linking. Previously we have reported that tyrosine-to-cysteine mutations, particularly at the tyrosine 39 residue (Y39C), significantly enhanced ␣-synuclein fibril formation and neurotoxicity. In the current study, we have generated transgenic mice expressing the Y39C mutant human ␣-synuclein gene controlled by the mouse Thy1 promoter. Mutant human ␣-synuclein was widely expressed in transgenic mouse brain, resulting in 150% overexpression relative to endogenous mouse ␣-synuclein. At age 9 -12 months, transgenic mice began to display motor dysfunction in rotarod testing. Older animals aged 15-18 months showed progressive accumulation of human ␣-synuclein oligomers, associated with worse motor function and cognitive impairment in the Morris water maze. By age 21-24 months, ␣-synuclein aggregates were further increased, accompanied by severe behavioral deficits. At this age, transgenic mice developed neuropathology, such as Lewy body-like ␣-synuclein and ubiquitin-positive inclusions, phosphorylation at Ser 129 of human ␣-synuclein, and increased apoptotic cell death. In summary, Y39C human ␣-synuclein transgenic mice show age-dependent, progressive neuronal degeneration with motor and cognitive deficits similar to diffuse Lewy body disease. The time course of ␣-synuclein oligomer accumulation coincided with behavioral and pathological changes, indicating that these oligomers may initiate protein aggregation, disrupt cellular function, and eventually lead to neuronal death.

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“…According to the manufacturer, a human α–synuclein cDNA sequence encoding a mutated protein with an Ala 53 Thr mutation and the mouse prion protein gene promoter, together with its 5′ and 3′ untranslated regions were used as the transgene to create α-SYN Tg mice on a C57BL/C3H background. The influence of different promoters on the expression pattern of mutated human α–synuclein in transgenic mice has been evaluated for Tg mice under the control of three different promoters: the chicken β-actin, the mouse tyrosine hydroxylase 9.6 kb and the mouse prion protein (Maskri et al, 2004). Although, all three promoters were found to successfully drive the expression of the transgene, the mouse prion protein promoter resulted in the highest level of transgene expression in the brain and specific neuron types (Maskri et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

“…The influence of different promoters on the expression pattern of mutated human α–synuclein in transgenic mice has been evaluated for Tg mice under the control of three different promoters: the chicken β-actin, the mouse tyrosine hydroxylase 9.6 kb and the mouse prion protein (Maskri et al, 2004). Although, all three promoters were found to successfully drive the expression of the transgene, the mouse prion protein promoter resulted in the highest level of transgene expression in the brain and specific neuron types (Maskri et al, 2004). Differences were noted in the transgene expression pattern in peripheral organs as well as the number and distribution of expressing cells in the brain (Maskri et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Autonomic dysfunction and plasticity in micturition reflexes in human α‐synuclein mice

Hamill

Tompkins

Girard

et al. 2012

Developmental Neurobiology

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Although often overshadowed by the motor dysfunction associated with Parkinson’s disease (PD), autonomic dysfunction including urinary bladder and bowel dysfunctions are often associated with PD and may precede motoric changes; such autonomic dysfunction may permit early detection and intervention. Lower urinary tract symptoms are common in PD patients and result in significant morbidity. The current studies focus on non-motor symptoms in PD using a transgenic mouse model with overexpression of human α-synuclein, the peptide found in high concentrations in Lewy body neuronal inclusions, the histopathologic hallmark of PD. We examined changes in the physiological, molecular, chemical, and electrical properties of neuronal pathways controlling urinary bladder function in transgenic mice. The results of these studies reveal that autonomic dysfunction (i.e., urinary bladder) can precede motor dysfunction. In addition, mice with human α-synuclein overexpression in relevant neuronal populations is associated with alterations in expression of neurotransmitter/ neuromodulatory molecules (PACAP, VIP, substance P, neuronal NOS) within neuronal pathways regulating bladder function as well as with increased NGF expression in the urinary bladder. Changes in the electrical and synaptic properties of neurons in the major pelvic ganglia that provide postganglionic innervation to urogenital tissues were not changed as determined with intracellular recording. The urinary bladder dysfunction observed in transgenic mice likely reflects changes in peripheral (i.e., afferent) and/or central micturition pathways or changes in the urinary bladder. SYN-OE mice provide an opportunity to examine early events underlying the molecular and cellular plasticity of autonomic nervous system pathways underlying synucleinopathies.

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Influence of Different Promoters on the Expression Pattern of Mutated Human α-Synuclein in Transgenic Mice

Cited by 37 publications

References 77 publications

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human α-Synuclein

Autonomic dysfunction and plasticity in micturition reflexes in human α‐synuclein mice

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