TY - JOUR
T1 - Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation
AU - Toft, Anders
AU - Sjödin, Simon
AU - Simonsen, Anja Hviid
AU - Ejlerskov, Patrick
AU - Roos, Peter
AU - Musaeus, Christian Sandøe
AU - Henriksen, Emil Elbæk
AU - Nielsen, Troels Tolstrup
AU - Brinkmalm, Ann
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Nielsen, Jørgen Erik
N1 - Funding Information:
K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003), Aase & Ejnar Danielsens Fond (19-10-0192), P.A. Messerschmidt & Hustrus Fond, Lægeforeningens Forskningsfond.
Funding Information:
K.B. is supported by the Swedish Research Council (#2017‐00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB‐201809‐2016615), the Swedish Alzheimer Foundation (#AF‐930351, #AF‐939721, and #AF‐968270), Hjärnfonden, Sweden (#FO2017‐0243 and #ALZ2022‐0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986 and #ALFGBG‐965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236), the National Institute of Health (NIH), USA, (grant #1R01AG068398‐01), and the Alzheimer's Association 2021 Zenith Award (ZEN‐21‐848495). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C, and #ADSF‐21‐831377‐C), the Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), and the UK Dementia Research Institute at UCL (UKDRI‐1003), Aase & Ejnar Danielsens Fond (19‐10‐0192), P.A. Messerschmidt & Hustrus Fond, Lægeforeningens Forskningsfond.
Publisher Copyright:
© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.
PY - 2023
Y1 - 2023
N2 - Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD). 31 members of the Danish CHMP2B-FTD family were included. We used solid-phase extraction and parallel reaction monitoring mass spectrometry. Six protein levels were significantly altered in CHMP2B-FTD compared with controls. Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.
AB - Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD). 31 members of the Danish CHMP2B-FTD family were included. We used solid-phase extraction and parallel reaction monitoring mass spectrometry. Six protein levels were significantly altered in CHMP2B-FTD compared with controls. Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.
KW - amyloid precursor protein
KW - biomarkers
KW - cathepsin B
KW - cerebrospinal fluid
KW - complement C9
KW - frontotemporal dementia
KW - lysozyme
KW - proteomics
KW - transcobalamin II
KW - ubiquitin
U2 - 10.1002/dad2.12402
DO - 10.1002/dad2.12402
M3 - Journal article
C2 - 36815874
AN - SCOPUS:85152370046
VL - 15
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
SN - 2352-8729
IS - 1
M1 - e12402
ER -