The novel adaptive rotating beam test unmasks sensorimotor impairments in a transgenic mouse model of Parkinson’s disease

Gerstenberger, Julia; Bauer, Anne; Helmschrodt, Christin; Richter, Angelika; Richter, Franziska

doi:10.1016/j.bbr.2016.02.017

Cited by 12 publications

(15 citation statements)

References 37 publications

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“… 46 , 47 In order to provide first evidence of nanoparticle efficacy and functionality, we chose a well-established mouse model of PD with overexpression of human SNCA under the Thy-1 promotor (Thy1-aSyn). 8 , 25 , 26 We demonstrate that a single ICV infusion of 0.75 μg PEI/SNCA-siRNA resulted in 67% reduction of SNCA mRNA in the striatum and ∼50% reduction in SNCA protein in all regions investigated (striatum, medial septum, and cortex). Thy1-aSyn mice overexpress human SNCA between 3- and 10-fold, depending on the brain region.…”

Section: Discussionmentioning

confidence: 70%

“…Female Thy1-aSyn transgenics are not suitable for this study due to their low and variable transgene expression. 26 …”

Section: Methodsmentioning

confidence: 99%

“…Expression of human wild-type SNCA mRNA was determined in striatal tissue of male Thy1-aSyn mice by qRT-PCR following the manufacturer’s protocol (QIAGEN, Venlo, the Netherlands) as described previously. 9 , 26 In brief, RNA was extracted using the RNeasy Plus Mini Kit (QIAGEN). First-strand cDNA synthesis was performed using PrimeScript RT Master Mix Perfect Real Time kit (Takara Bio Clontech Laboratories, CA, USA) and random primers according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…In the context of a proof-of-concept study with therapeutic implication, we silenced SNCA in the Thy1-aSyn transgenic mouse model of PD. 8 , 25 , 26 Our approach includes analyses of knockdown efficacy and biocompatibility/absence of toxicity of the PEI/siRNA complexes (1) in vitro in the neuroblastoma cell line SH-SY5Y and (2) in vivo after intracerebroventricular (ICV) injection in Thy1-aSyn mice. Efficacy was determined by specific mRNA knockdown of human SNCA and the verification at protein level.…”

Section: Introductionmentioning

confidence: 99%

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Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson’s Disease

Helmschrodt

Höbel

Schöniger

et al. 2017

Molecular Therapy - Nucleic Acids

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123

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RNA interference (RNAi)-based strategies that mediate the specific knockdown of target genes by administration of small interfering RNAs (siRNAs) could be applied for treatment of presently incurable neurodegenerative diseases such as Parkinson’s disease. However, inefficient delivery of siRNA into neurons hampers in vivo application of RNAi. We have previously established the 4–12 kDa branched polyethylenimine (PEI) F25-LMW with superior transfection efficacy for delivery of siRNA in vivo. Here, we present that siRNA complexed with this PEI extensively distributes across the CNS down to the lumbar spinal cord after a single intracerebroventricular infusion. siRNA against α-synuclein (SNCA), a pre-synaptic protein that aggregates in Parkinson’s disease, was complexed with PEI F25-LMW and injected into the lateral ventricle of mice overexpressing human wild-type SNCA (Thy1-aSyn mice). Five days after the single injection of 0.75 μg PEI/siRNA, SNCA mRNA expression in the striatum was reduced by 65%, accompanied by reduction of SNCA protein by ∼50%. Mice did not show signs of toxicity or adverse effects. Moreover, ependymocytes and brain parenchyma were completely preserved and free of immune cell invasion, astrogliosis, or microglial activation. Our results support the efficacy and safety of PEI nanoparticle-mediated delivery of siRNA to the brain for therapeutic intervention.

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Section: Discussionmentioning

confidence: 70%

“…Female Thy1-aSyn transgenics are not suitable for this study due to their low and variable transgene expression. 26 …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson’s Disease

Helmschrodt

Höbel

Schöniger

et al. 2017

Molecular Therapy - Nucleic Acids

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123

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“…α-synuclein transgenic female mice are known to outperform males on sensorimotor tests (7,51,66) and display changes in the expression of greater numbers of genes than male mice (171). However, sex-dependent differences in α-synuclein histopathology in the brain remain poorly understood, partly because females express approximately half as much wildtype human α-synuclein mRNA in the substantia nigra as male mice when α-synuclein expression is driven by the Thy1 promoter (66). Thus, a second goal of the present study was to test the impact of gender on the regional distribution and density of α-synuclein + inclusions and on cell loss in 16 key brain regions, 6 months following infusions of the same dose of preformed α-synuclein fibrils into the OB/AON of 3-month-old male and female nontransgenic mice.…”

Section: Introductionmentioning

confidence: 99%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

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Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

Schidlitzki¹,

Stanojlović²,

Fournier

et al. 2023

Movement Disorders

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A BS TRACT: Background: Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). Objective: The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type α-synuclein. Methods: Mice overexpressing α-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of α-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, α-synuclein-related pathology, and microgliosis were compared with untreated controls. Results: Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound α-synuclein in the striatum and phosphorylated α-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated α-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gbadeficient model with nigral α-synuclein overexpression and neurodegeneration. Conclusions: Venglustat treatment in two mouse models of α-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects.

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The novel adaptive rotating beam test unmasks sensorimotor impairments in a transgenic mouse model of Parkinson’s disease

Cited by 12 publications

References 37 publications

Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson’s Disease

Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce α-Synuclein Expression in a Model of Parkinson’s Disease

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

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