Poul Henning Jensen

Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. / Rockenstein, Edward; Nuber, Silke; Overk, Cassia R; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H; Campioni, Silvia; Riek, Roland; Winkler, Jürgen; Gage, Fred H; Winner, Beate; Masliah, Eliezer.

In: Brain, Vol. 137, No. Pt 5, 05.2014, p. 1496-513.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Rockenstein, E, Nuber, S, Overk, CR, Ubhi, K, Mante, M, Patrick, C, Adame, A, Trejo-Morales, M, Gerez, J, Picotti, P, Jensen, PH, Campioni, S, Riek, R, Winkler, J, Gage, FH, Winner, B & Masliah, E 2014, 'Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo', Brain, vol. 137, no. Pt 5, pp. 1496-513. https://doi.org/10.1093/brain/awu057

APA

Rockenstein, E., Nuber, S., Overk, C. R., Ubhi, K., Mante, M., Patrick, C., ... Masliah, E. (2014). Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain, 137(Pt 5), 1496-513. https://doi.org/10.1093/brain/awu057

CBE

Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Trejo-Morales M, Gerez J, Picotti P, Jensen PH, Campioni S, Riek R, Winkler J, Gage FH, Winner B, Masliah E. 2014. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 137(Pt 5):1496-513. https://doi.org/10.1093/brain/awu057

MLA

Vancouver

Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C et al. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 2014 May;137(Pt 5):1496-513. https://doi.org/10.1093/brain/awu057

Author

Rockenstein, Edward ; Nuber, Silke ; Overk, Cassia R ; Ubhi, Kiren ; Mante, Michael ; Patrick, Christina ; Adame, Anthony ; Trejo-Morales, Margarita ; Gerez, Juan ; Picotti, Paola ; Jensen, Poul H ; Campioni, Silvia ; Riek, Roland ; Winkler, Jürgen ; Gage, Fred H ; Winner, Beate ; Masliah, Eliezer. / Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. In: Brain. 2014 ; Vol. 137, No. Pt 5. pp. 1496-513.

Bibtex

@article{a55f694f7f264f31a137127c19a0d481,
title = "Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo",
abstract = "In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.",
keywords = "Alzheimer Disease, Animals, Antigens, Thy-1, Brain, Disease Models, Animal, Gene Expression Regulation, Glutamic Acid, Humans, Lewy Body Disease, Lysine, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Neurons, Synapses, alpha-Synuclein",
author = "Edward Rockenstein and Silke Nuber and Overk, {Cassia R} and Kiren Ubhi and Michael Mante and Christina Patrick and Anthony Adame and Margarita Trejo-Morales and Juan Gerez and Paola Picotti and Jensen, {Poul H} and Silvia Campioni and Roland Riek and J{\"u}rgen Winkler and Gage, {Fred H} and Beate Winner and Eliezer Masliah",
year = "2014",
month = "5",
doi = "10.1093/brain/awu057",
language = "English",
volume = "137",
pages = "1496--513",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "Pt 5",

}

RIS

TY - JOUR

T1 - Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

AU - Rockenstein, Edward

AU - Nuber, Silke

AU - Overk, Cassia R

AU - Ubhi, Kiren

AU - Mante, Michael

AU - Patrick, Christina

AU - Adame, Anthony

AU - Trejo-Morales, Margarita

AU - Gerez, Juan

AU - Picotti, Paola

AU - Jensen, Poul H

AU - Campioni, Silvia

AU - Riek, Roland

AU - Winkler, Jürgen

AU - Gage, Fred H

AU - Winner, Beate

AU - Masliah, Eliezer

PY - 2014/5

Y1 - 2014/5

N2 - In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.

AB - In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.

KW - Alzheimer Disease

KW - Animals

KW - Antigens, Thy-1

KW - Brain

KW - Disease Models, Animal

KW - Gene Expression Regulation

KW - Glutamic Acid

KW - Humans

KW - Lewy Body Disease

KW - Lysine

KW - Memory Disorders

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Mutation

KW - Nerve Degeneration

KW - Nerve Tissue Proteins

KW - Neurons

KW - Synapses

KW - alpha-Synuclein

U2 - 10.1093/brain/awu057

DO - 10.1093/brain/awu057

M3 - Journal article

C2 - 24662516

VL - 137

SP - 1496

EP - 1513

JO - Brain

JF - Brain

SN - 0006-8950

IS - Pt 5

ER -