Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease

Silke Frahm, Valeria Melis, David Horsley, Janet E Rickard, Gernot Riedel (Corresponding Author), Paula Fadda, Maria Scherma, Charles R Harrington, Claude M Wischik, Franz Theuring (Corresponding Author), Karima Schwab

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Abstract

Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum. Interestingly, there was no detectable α-Syn expression in dopaminergic neurones of the substantia nigra, but strong human α-Syn reactivity in glutamatergic synapses. The human α-Syn accumulated during aging and formed PK-resistant, thioflavin-binding aggregates. Mice displayed early onset bradykinesia and age progressive motor deficits. Functional alterations within the striatum were confirmed: L62 showed normal basal dopamine levels, but impaired dopamine release (upon amphetamine challenge) in the dorsal striatum measured by in vivo brain dialysis at 9 months of age. This impairment was coincident with a reduced response to amphetamine in the activity test. L62 further displayed greater sensitivity to low doses of the dopamine receptor 1 (D1) agonist SKF81297 but reacted normally to the D2 agonist quinpirole in the open field. Since accumulation of α-Syn aggregates in neurones and synapses and alterations in the dopaminergic tone are characteristics of PD, phenotypes reported for L62 present a good opportunity to further our understanding of motor dysfunction in PD and Lewy body dementia.

Original languageEnglish
Pages (from-to)153-168
Number of pages16
JournalBehavioural Brain Research
Volume339
Early online date24 Nov 2017
DOIs
Publication statusPublished - 26 Feb 2018

Fingerprint

alpha-Synuclein
Transgenic Mice
Parkinson Disease
Lewy Body Disease
Amphetamine
Phenotype
Synapses
Dopamine
Quinpirole
Hypokinesia
Dopaminergic Neurons
Dopamine Agonists
Brain
Substantia Nigra
Protein Sorting Signals
Age of Onset
Dialysis
Spinal Cord
Gene Expression
Neurons

Keywords

  • Journal Article
  • α-Synuclein
  • protein aggregation
  • Parkinson’s disease
  • motor dysfunction
  • glutamate

Cite this

@article{611b9a21d78641d288e7fa1fef94e1ac,
title = "Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease",
abstract = "Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum. Interestingly, there was no detectable α-Syn expression in dopaminergic neurones of the substantia nigra, but strong human α-Syn reactivity in glutamatergic synapses. The human α-Syn accumulated during aging and formed PK-resistant, thioflavin-binding aggregates. Mice displayed early onset bradykinesia and age progressive motor deficits. Functional alterations within the striatum were confirmed: L62 showed normal basal dopamine levels, but impaired dopamine release (upon amphetamine challenge) in the dorsal striatum measured by in vivo brain dialysis at 9 months of age. This impairment was coincident with a reduced response to amphetamine in the activity test. L62 further displayed greater sensitivity to low doses of the dopamine receptor 1 (D1) agonist SKF81297 but reacted normally to the D2 agonist quinpirole in the open field. Since accumulation of α-Syn aggregates in neurones and synapses and alterations in the dopaminergic tone are characteristics of PD, phenotypes reported for L62 present a good opportunity to further our understanding of motor dysfunction in PD and Lewy body dementia.",
keywords = "Journal Article, α-Synuclein, protein aggregation, Parkinson’s disease , motor dysfunction, glutamate",
author = "Silke Frahm and Valeria Melis and David Horsley and Rickard, {Janet E} and Gernot Riedel and Paula Fadda and Maria Scherma and Harrington, {Charles R} and Wischik, {Claude M} and Franz Theuring and Karima Schwab",
note = "Acknowledgments: The authors acknowledge Mandy Magbagbeolu and Heide Lueck for excellent technical assistance and Anna Thoma for assistance in behavioural testing and maintenance of animals. This work was funded by TauRx Therapeutics Ltd., Singapore. C.R.H. and C.M.W. declare that they are officers in TauRx Therapeutics Ltd.",
year = "2018",
month = "2",
day = "26",
doi = "10.1016/j.bbr.2017.11.025",
language = "English",
volume = "339",
pages = "153--168",
journal = "Behavioural Brain Research",
issn = "0166-4328",
publisher = "Elsevier",

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TY - JOUR

T1 - Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease

AU - Frahm, Silke

AU - Melis, Valeria

AU - Horsley, David

AU - Rickard, Janet E

AU - Riedel, Gernot

AU - Fadda, Paula

AU - Scherma, Maria

AU - Harrington, Charles R

AU - Wischik, Claude M

AU - Theuring, Franz

AU - Schwab, Karima

N1 - Acknowledgments: The authors acknowledge Mandy Magbagbeolu and Heide Lueck for excellent technical assistance and Anna Thoma for assistance in behavioural testing and maintenance of animals. This work was funded by TauRx Therapeutics Ltd., Singapore. C.R.H. and C.M.W. declare that they are officers in TauRx Therapeutics Ltd.

PY - 2018/2/26

Y1 - 2018/2/26

N2 - Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum. Interestingly, there was no detectable α-Syn expression in dopaminergic neurones of the substantia nigra, but strong human α-Syn reactivity in glutamatergic synapses. The human α-Syn accumulated during aging and formed PK-resistant, thioflavin-binding aggregates. Mice displayed early onset bradykinesia and age progressive motor deficits. Functional alterations within the striatum were confirmed: L62 showed normal basal dopamine levels, but impaired dopamine release (upon amphetamine challenge) in the dorsal striatum measured by in vivo brain dialysis at 9 months of age. This impairment was coincident with a reduced response to amphetamine in the activity test. L62 further displayed greater sensitivity to low doses of the dopamine receptor 1 (D1) agonist SKF81297 but reacted normally to the D2 agonist quinpirole in the open field. Since accumulation of α-Syn aggregates in neurones and synapses and alterations in the dopaminergic tone are characteristics of PD, phenotypes reported for L62 present a good opportunity to further our understanding of motor dysfunction in PD and Lewy body dementia.

AB - Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum. Interestingly, there was no detectable α-Syn expression in dopaminergic neurones of the substantia nigra, but strong human α-Syn reactivity in glutamatergic synapses. The human α-Syn accumulated during aging and formed PK-resistant, thioflavin-binding aggregates. Mice displayed early onset bradykinesia and age progressive motor deficits. Functional alterations within the striatum were confirmed: L62 showed normal basal dopamine levels, but impaired dopamine release (upon amphetamine challenge) in the dorsal striatum measured by in vivo brain dialysis at 9 months of age. This impairment was coincident with a reduced response to amphetamine in the activity test. L62 further displayed greater sensitivity to low doses of the dopamine receptor 1 (D1) agonist SKF81297 but reacted normally to the D2 agonist quinpirole in the open field. Since accumulation of α-Syn aggregates in neurones and synapses and alterations in the dopaminergic tone are characteristics of PD, phenotypes reported for L62 present a good opportunity to further our understanding of motor dysfunction in PD and Lewy body dementia.

KW - Journal Article

KW - α-Synuclein

KW - protein aggregation

KW - Parkinson’s disease

KW - motor dysfunction

KW - glutamate

U2 - 10.1016/j.bbr.2017.11.025

DO - 10.1016/j.bbr.2017.11.025

M3 - Article

VL - 339

SP - 153

EP - 168

JO - Behavioural Brain Research

JF - Behavioural Brain Research

SN - 0166-4328

ER -