Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

Claire Bridel; Juami H.M. van Gils; Suzanne S.M. Miedema; Jeroen J.M. Hoozemans; Yolande A.L. Pijnenburg; August B. Smit; Annemieke J.M. Rozemuller; Sanne Abeln; Charlotte E. Teunissen

doi:10.1186/s13195-023-01200-1

Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

Claire Bridel, Juami H.M. van Gils^*, Suzanne S.M. Miedema, Jeroen J.M. Hoozemans, Yolande A.L. Pijnenburg, August B. Smit, Annemieke J.M. Rozemuller, Sanne Abeln, Charlotte E. Teunissen^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods: To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results: The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. Conclusions: Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.

Original language	English
Article number	59
Pages (from-to)	1-18
Number of pages	18
Journal	Alzheimer's Research and Therapy
Volume	15
DOIs	https://doi.org/10.1186/s13195-023-01200-1
Publication status	Published - 23 Mar 2023

Bibliographical note

Funding Information:
We thank the Dutch Brain Bank for providing the brain samples. We thank Dr. Ka Wan Li and Dr. Frank Koopmans from the Vrije Universiteit Amsterdam for performing the mass spectrometry experimental work and analysis.

Funding Information:
CB and CET thank the ZonMW for funding the PRODIA project (project number 733050206). JvG and SA thank the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ( https://www.nwo.nl/over-nwo/organisatie/nwo-onderdelen/enw ) for funding under project number 680-91-112 (NWO).

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank the Dutch Brain Bank for providing the brain samples. We thank Dr. Ka Wan Li and Dr. Frank Koopmans from the Vrije Universiteit Amsterdam for performing the mass spectrometry experimental work and analysis. CB and CET thank the ZonMW for funding the PRODIA project (project number 733050206). JvG and SA thank the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ( https://www.nwo.nl/over-nwo/organisatie/nwo-onderdelen/enw ) for funding under project number 680-91-112 (NWO).

Funders	Funder number
Dutch Brain Bank
ZonMw	733050206
ZonMw
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	680-91-112
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

CDK5
Chromatin regulation
Clathrin-mediated transport
Co-expression module
Dementia
Frontotemporal lobar degeneration
PTBP1
Tau
TDP43
Tissue proteomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13195-023-01200-1

Persistent URL (handle)

Copy link address

Cite this

Bridel, C., van Gils, J. H. M., Miedema, S. S. M., Hoozemans, J. J. M., Pijnenburg, Y. A. L., Smit, A. B., Rozemuller, A. J. M., Abeln, S., & Teunissen, C. E. (2023). Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration. Alzheimer's Research and Therapy, 15, 1-18. Article 59. https://doi.org/10.1186/s13195-023-01200-1

@article{cbeee9f26fcb4bd3ae4e3cdcad5d7eff,

title = "Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration",

abstract = "Background: Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods: To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results: The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. Conclusions: Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.",

keywords = "CDK5, Chromatin regulation, Clathrin-mediated transport, Co-expression module, Dementia, Frontotemporal lobar degeneration, PTBP1, Tau, TDP43, Tissue proteomics",

author = "Claire Bridel and {van Gils}, {Juami H.M.} and Miedema, {Suzanne S.M.} and Hoozemans, {Jeroen J.M.} and Pijnenburg, {Yolande A.L.} and Smit, {August B.} and Rozemuller, {Annemieke J.M.} and Sanne Abeln and Teunissen, {Charlotte E.}",

note = "Funding Information: We thank the Dutch Brain Bank for providing the brain samples. We thank Dr. Ka Wan Li and Dr. Frank Koopmans from the Vrije Universiteit Amsterdam for performing the mass spectrometry experimental work and analysis. Funding Information: CB and CET thank the ZonMW for funding the PRODIA project (project number 733050206). JvG and SA thank the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ( https://www.nwo.nl/over-nwo/organisatie/nwo-onderdelen/enw ) for funding under project number 680-91-112 (NWO). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

day = "23",

doi = "10.1186/s13195-023-01200-1",

language = "English",

volume = "15",

pages = "1--18",

journal = "Alzheimer's Research and Therapy",

issn = "1758-9193",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

AU - Bridel, Claire

AU - van Gils, Juami H.M.

AU - Miedema, Suzanne S.M.

AU - Hoozemans, Jeroen J.M.

AU - Pijnenburg, Yolande A.L.

AU - Smit, August B.

AU - Rozemuller, Annemieke J.M.

AU - Abeln, Sanne

AU - Teunissen, Charlotte E.

N1 - Funding Information: We thank the Dutch Brain Bank for providing the brain samples. We thank Dr. Ka Wan Li and Dr. Frank Koopmans from the Vrije Universiteit Amsterdam for performing the mass spectrometry experimental work and analysis. Funding Information: CB and CET thank the ZonMW for funding the PRODIA project (project number 733050206). JvG and SA thank the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ( https://www.nwo.nl/over-nwo/organisatie/nwo-onderdelen/enw ) for funding under project number 680-91-112 (NWO). Publisher Copyright: © 2023, The Author(s).

PY - 2023/3/23

Y1 - 2023/3/23

N2 - Background: Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods: To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results: The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. Conclusions: Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.

AB - Background: Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods: To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results: The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. Conclusions: Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.

KW - CDK5

KW - Chromatin regulation

KW - Clathrin-mediated transport

KW - Co-expression module

KW - Dementia

KW - Frontotemporal lobar degeneration

KW - PTBP1

KW - Tau

KW - TDP43

KW - Tissue proteomics

UR - http://www.scopus.com/inward/record.url?scp=85150758458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85150758458&partnerID=8YFLogxK

U2 - 10.1186/s13195-023-01200-1

DO - 10.1186/s13195-023-01200-1

M3 - Article

C2 - 36949537

AN - SCOPUS:85150758458

SN - 1758-9193

VL - 15

SP - 1

EP - 18

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

M1 - 59

ER -

Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this