Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation

Gispert, Suzana; Turco, Domenico Del; Garrett, Lisa; Chen, Amy; Bernard, David; Hamm-Clement, John; Korf, Horst‐Werner; Deller, Thomas; Braak, Heiko; Auburger, Georg; Nussbaum, Robert L.

doi:10.1016/s1044-7431(03)00198-2

Cited by 183 publications

(162 citation statements)

References 36 publications

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“…Consistent with findings in previously published ␣-syn tg mice (Masliah et al, 2000;Matsuoka et al, 2001;Richfield et al, 2002;Rockenstein et al, 2002;Gispert et al, 2003;Tofaris et al, 2006), human ␣-syn protein was also localized in the cytoplasm of nigral dopaminergic neurons. Electron microscopical analyses revealed prominent accumulation of tg ␣-syn in nigral axons and association of human ␣-syn with lysosomes.…”

Section: Discussionsupporting

confidence: 92%

“…Microscopically, proteinacious inclusions, termed "Lewy bodies" (LBs) are frequently detected in remaining nigral neurons of postmortem PD brains. The presence of these cytoplasmatic inclusions might be cytotoxic (Hurtig et al, 2000;Giasson et al, 2002;Braak et al, 2004), but there is increasing evidence that, in contrast, they might be cytoprotective by sequestering toxic protein structures (Gispert et al, 2003;Tanaka et al, 2004;Inden et al, 2005;Bodner et al, 2006). ␣-Synuclein (␣-syn) was identified as the major filamentous component of LBs (Spillantini et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

160

133

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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: 92%

Section: Introductionmentioning

confidence: 99%

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

Nuber¹,

Petrasch‐Parwez²,

Winner³

et al. 2008

J. Neurosci.

160

133

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“…Analysis of α‐synuclein protein levels in different brain regions of SNCA/SNCA mice demonstrated approximately 50% increase in α‐synuclein levels compared to wild‐type mice in the brainstem, cortex, and striatum. The observed increase was comparable to that previously reported, where a 1‐ to 1.5‐fold increase in α‐synuclein protein expression was observed, when compared to wild‐type endogenous mouse α‐synuclein levels 31. We also observed a significant increase in S129 phosphorylation of α‐synuclein in the brainstem, cortex, and striatum of our SNCA/SNCA mice compared to that in wild‐type mice.…”

Section: Discussionsupporting

confidence: 90%

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Migdalska‐Richards

Daly

Bézard

et al. 2016

Annals of Neurology

151

138

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ObjectiveGaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α‐synuclein and phosphorylated α‐synuclein protein levels in mice.MethodsMice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α‐synuclein and phosphorylated α‐synuclein protein levels.ResultsAmbroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild‐type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α‐synuclein. Furthermore, in the mice overexpressing human α‐synuclein, ambroxol treatment decreased both α‐synuclein and phosphorylated α‐synuclein protein levels.InterpretationOur work supports the proposition that ambroxol should be further investigated as a potential novel disease‐modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α‐synuclein and phosphorylated α‐synuclein protein levels. Ann Neurol 2016;80:766–775

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“…ASO animals became worse on the challenging beam beginning at 6 months, indicating that the motor deficit was progressive. Motor performance was also altered in another ␣-synuclein overexpressing mouse, although the age of onset of these deficits was not specified (Gispert et al, 2003). ASO mice also showed a deficit in their response to sensory stimuli.…”

Section: Aso Mice Exhibit An Early and Progressive Behavioral Phenotypementioning

confidence: 99%

“…The most common tests used, the rotarod and automated activity monitoring, lack sensitivity to subtle alterations in the nigrostriatal system (Tillerson et al, 2002a;Goldberg et al, 2003). Indeed, previous studies have shown that unless the transgene affects motoneurons, mice overexpressing ␣-synuclein do not show motor alterations until 8 -12 months of age (Masliah et al, 2000;Richfield et al, 2002), except for one report of an early decrease in spontaneous rearing that precedes much later alterations on the rotarod (Gispert et al, 2003). Transgenic mice overexpressing human wild-type ␣-synuclein under the Thy-1 promoter have high levels of ␣-synuclein expression in neurons and ␣-synuclein accumulation in brain, including the substantia nigra but not the spinal cord or neuromuscular junction (Rockenstein et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein

Fleming¹,

Salcedo²,

Fernagut³

et al. 2004

J. Neurosci.

433

467

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Accumulation of ␣-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing ␣-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of ␣-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of ␣-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

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Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation

Cited by 183 publications

References 36 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

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein

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