Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease
Sjödin, Simon ; Brinkmalm, Gunnar ; Öhrfelt, Annika ; Parnetti, Lucilla ; Paciotti, Silvia ; Hansson, Oskar LU
; Hardy, John
; Blennow, Kaj
LU
; Zetterberg, Henrik
LU
and Brinkmalm, Ann
(2019)
In Alzheimer's Research and Therapy
11(1).
- Abstract
Background: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. Methods: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining... (More)
Background: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. Methods: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). Results: A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. Conclusion: In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.
(Less)
- author
- Sjödin, Simon
; Brinkmalm, Gunnar
; Öhrfelt, Annika
; Parnetti, Lucilla
; Paciotti, Silvia
; Hansson, Oskar
LU
; Hardy, John
; Blennow, Kaj
LU
; Zetterberg, Henrik
LU
and Brinkmalm, Ann
- organization
- publishing date
- 2019-09-14
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer's disease, Biomarker, CSF, Mass spectrometry, Parkinson's disease
- in
- Alzheimer's Research and Therapy
- volume
- 11
- issue
- 1
- article number
- 82
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:31521194
- scopus:85072196753
- ISSN
- 1758-9193
- DOI
- 10.1186/s13195-019-0533-9
- language
- English
- LU publication?
- yes
- id
- 2a9ff9e7-f145-417f-a0bf-3b62e4cc62a9
- date added to LUP
- 2019-10-01 11:02:05
- date last changed
- 2024-04-30 21:58:37
@article{2a9ff9e7-f145-417f-a0bf-3b62e4cc62a9,
abstract = {{<p>Background: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. Methods: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). Results: A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. Conclusion: In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.</p>}},
author = {{Sjödin, Simon and Brinkmalm, Gunnar and Öhrfelt, Annika and Parnetti, Lucilla and Paciotti, Silvia and Hansson, Oskar and Hardy, John and Blennow, Kaj and Zetterberg, Henrik and Brinkmalm, Ann}},
issn = {{1758-9193}},
keywords = {{Alzheimer's disease; Biomarker; CSF; Mass spectrometry; Parkinson's disease}},
language = {{eng}},
month = {{09}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Alzheimer's Research and Therapy}},
title = {{Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease}},
url = {{http://dx.doi.org/10.1186/s13195-019-0533-9}},
doi = {{10.1186/s13195-019-0533-9}},
volume = {{11}},
year = {{2019}},
}