Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

Anders Toft; Simon Sjödin; Anja Hviid Simonsen; Patrick Ejlerskov; Peter Roos; Christian Sandøe Musaeus; Emil Elbæk Henriksen; Troels Tolstrup Nielsen; Ann Brinkmalm; Kaj Blennow; Henrik Zetterberg; Jørgen Erik Nielsen

doi:10.1002/dad2.12402

Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

Alzheimers Dement (Amst). 2023 Feb 16;15(1):e12402. doi: 10.1002/dad2.12402. eCollection 2023 Jan-Mar.

Authors

Affiliations

¹ Neurogenetics Clinic & Research Lab Danish Dementia Research Centre Rigshospitalet Copenhagen Denmark.
² Laboratory of Clinical Chemistry Sahlgrenska University Hospital Gothenburg Sweden.
³ Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden.
⁴ Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden.
⁵ Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK.
⁶ UK Dementia Research Institute at UCL London UK.
⁷ Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Hong Kong China.

Abstract

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.

Keywords: amyloid precursor protein; biomarkers; cathepsin B; cerebrospinal fluid; complement C9; frontotemporal dementia; lysozyme; proteomics; transcobalamin II; ubiquitin.