Synaptic phosphorylated α-synuclein in dementia with Lewy bodies

Marti Colom-Cadena, Jordi Pequeroles, Abigail Herrmann, Christopher Henstridge, Laia Munoz-Llahuna, Marta Querol-Vilaseca, Carla San Martín-Paniello, Joan Luque-Cabecerans, Jordi Clarimon, Olivia Belbin, Raul Núñez-Llaves, Rafael Blesa, Colin Smith, Chris-Anne McKenzie, Matthew Frosch, Allyson D Roe, Juan Fortea, Jordi Andilla, Pablo Loza-Alvarez , Ellen Gelpi & 3 others Bradley Hyman, Tara Spires-Jones, Alberto Lleo

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.
Original languageEnglish
Pages (from-to)3204-3214
Number of pages11
JournalBrain
Volume140
Issue number12
DOIs
Publication statusPublished - 21 Nov 2017

Fingerprint

Synucleins
Lewy Body Disease
Synapses
Lewy Bodies
Neurites
Tomography
Poisons
Gyrus Cinguli
Presynaptic Terminals
Fluorescent Antibody Technique
Microscopy
Healthy Volunteers
Alzheimer Disease
Pathology

Keywords

  • p-a-synuclein
  • dementia with Lewy bodies
  • synapses
  • array tomography
  • human tissue

Cite this

Colom-Cadena, M., Pequeroles, J., Herrmann, A., Henstridge, C., Munoz-Llahuna, L., Querol-Vilaseca, M., ... Lleo, A. (2017). Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain, 140(12), 3204-3214. https://doi.org/10.1093/brain/awx275
Colom-Cadena, Marti ; Pequeroles, Jordi ; Herrmann, Abigail ; Henstridge, Christopher ; Munoz-Llahuna, Laia ; Querol-Vilaseca, Marta ; San Martín-Paniello, Carla ; Luque-Cabecerans, Joan ; Clarimon, Jordi ; Belbin, Olivia ; Núñez-Llaves, Raul ; Blesa, Rafael ; Smith, Colin ; McKenzie, Chris-Anne ; Frosch, Matthew ; Roe, Allyson D ; Fortea, Juan ; Andilla, Jordi ; Loza-Alvarez , Pablo ; Gelpi, Ellen ; Hyman, Bradley ; Spires-Jones, Tara ; Lleo, Alberto. / Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. In: Brain. 2017 ; Vol. 140, No. 12. pp. 3204-3214.
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abstract = "Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19{\%} and 25{\%} of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.",
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author = "Marti Colom-Cadena and Jordi Pequeroles and Abigail Herrmann and Christopher Henstridge and Laia Munoz-Llahuna and Marta Querol-Vilaseca and {San Mart{\'i}n-Paniello}, Carla and Joan Luque-Cabecerans and Jordi Clarimon and Olivia Belbin and Raul N{\'u}{\~n}ez-Llaves and Rafael Blesa and Colin Smith and Chris-Anne McKenzie and Matthew Frosch and Roe, {Allyson D} and Juan Fortea and Jordi Andilla and Pablo Loza-Alvarez and Ellen Gelpi and Bradley Hyman and Tara Spires-Jones and Alberto Lleo",
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Colom-Cadena, M, Pequeroles, J, Herrmann, A, Henstridge, C, Munoz-Llahuna, L, Querol-Vilaseca, M, San Martín-Paniello, C, Luque-Cabecerans, J, Clarimon, J, Belbin, O, Núñez-Llaves, R, Blesa, R, Smith, C, McKenzie, C-A, Frosch, M, Roe, AD, Fortea, J, Andilla, J, Loza-Alvarez , P, Gelpi, E, Hyman, B, Spires-Jones, T & Lleo, A 2017, 'Synaptic phosphorylated α-synuclein in dementia with Lewy bodies', Brain, vol. 140, no. 12, pp. 3204-3214. https://doi.org/10.1093/brain/awx275

Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. / Colom-Cadena, Marti; Pequeroles, Jordi; Herrmann, Abigail; Henstridge, Christopher; Munoz-Llahuna, Laia; Querol-Vilaseca, Marta; San Martín-Paniello, Carla; Luque-Cabecerans, Joan; Clarimon, Jordi; Belbin, Olivia; Núñez-Llaves, Raul; Blesa, Rafael; Smith, Colin; McKenzie, Chris-Anne; Frosch, Matthew; Roe, Allyson D; Fortea, Juan; Andilla, Jordi; Loza-Alvarez , Pablo; Gelpi, Ellen; Hyman, Bradley; Spires-Jones, Tara; Lleo, Alberto.

In: Brain, Vol. 140, No. 12, 21.11.2017, p. 3204-3214.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synaptic phosphorylated α-synuclein in dementia with Lewy bodies

AU - Colom-Cadena, Marti

AU - Pequeroles, Jordi

AU - Herrmann, Abigail

AU - Henstridge, Christopher

AU - Munoz-Llahuna, Laia

AU - Querol-Vilaseca, Marta

AU - San Martín-Paniello, Carla

AU - Luque-Cabecerans, Joan

AU - Clarimon, Jordi

AU - Belbin, Olivia

AU - Núñez-Llaves, Raul

AU - Blesa, Rafael

AU - Smith, Colin

AU - McKenzie, Chris-Anne

AU - Frosch, Matthew

AU - Roe, Allyson D

AU - Fortea, Juan

AU - Andilla, Jordi

AU - Loza-Alvarez , Pablo

AU - Gelpi, Ellen

AU - Hyman, Bradley

AU - Spires-Jones, Tara

AU - Lleo, Alberto

PY - 2017/11/21

Y1 - 2017/11/21

N2 - Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

AB - Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

KW - p-a-synuclein

KW - dementia with Lewy bodies

KW - synapses

KW - array tomography

KW - human tissue

U2 - 10.1093/brain/awx275

DO - 10.1093/brain/awx275

M3 - Article

VL - 140

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EP - 3214

JO - Brain

JF - Brain

SN - 0006-8950

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Colom-Cadena M, Pequeroles J, Herrmann A, Henstridge C, Munoz-Llahuna L, Querol-Vilaseca M et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017 Nov 21;140(12):3204-3214. https://doi.org/10.1093/brain/awx275