Dataset Information

Endo-Lysosomal Proteins and Ubiquitin CSF Concentrations in Alzheimer’s and Parkinson’s Disease

ABSTRACT: Alzheimer’s (AD) and Parkinson’s disease (PD) are neurodegenerative disorders characterized by an accumulation of protein aggregates in the brain. AD is the most common cause of dementia and presents with impairment of memory and cognition. PD results from the loss of dopaminergic neurons which results in motor symptoms such as bradykinesia, rest tremor and/or rigidity. In AD and PD neuropathological investigation and genetic association indicate dysfunctional proteostasis as a pathological feature. Proteostasis is maintained by autophagy and the endosomal-lysosomal system and by the ubiquitin-proteasome system. We aimed to investigate new potential cerebrospinal fluid (CSF) biomarkers by targeting proteins involved in proteostasis. Measurable changes in protein concentrations in CSF might reflect altered proteostasis in neurodegenerative diseases. We identified and targeted 50 peptides from 18 proteins by combining solid-phase extraction (SPE) and parallel reaction monitoring mass spectrometry (PRM MS). The CSF concentration of these proteins were measured in four cross-sectional studies including subjects with AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (stable MCI; N = 15), as well as controls (N = 68). Two pilot studies (Study 1 and 2) showed increased concentrations of several proteins in subjects with biochemical evidence of AD pathology compared to biochemically characterized normal subjects. A study (Study 3) including clinically characterized subjects instead showed decreased CSF concentration of several proteins in PD compared to prodromal AD. A follow up cohort (Study 4) was analyzed, also including clinically characterized subjects. Again decreased CSF concentrations were identified in PD compared to controls and AD. Proteins identified with significant different protein concentrations in the studies were AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins with repeatedly identified significant differences in concentration, in more than one study, were AP2B1, CTSB, CTSF, GM2A, and ubiquitin. No differences in CSF concentration of the investigated proteins were identified in clinically characterized cases with AD compared to controls suggesting if such differences exist, compared to PD, are minor. Further studies are need to investigate whether the promising protein candidates identified herein might serve as potential CSF biomarkers in PD.

ORGANISM(S): Homo Sapiens

SUBMITTER: Simon Sjödin

PROVIDER: PXD013451 | panorama | Sun Oct 27 00:00:00 BST 2019

REPOSITORIES: PanoramaPublic

ACCESS DATA

Publications

Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease.

Sjödin Simon S Brinkmalm Gunnar G Öhrfelt Annika A Parnetti Lucilla L Paciotti Silvia S Hansson Oskar O Hardy John J Blennow Kaj K Zetterberg Henrik H Brinkmalm Ann A

Alzheimer's research & therapy 20190914 1

<h4>Background</h4>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, ...[more]

PMID: 31521194

Similar Datasets

Project description:Parkinson’s disease (PD) is a prevalent and incurable neurodegenerative disease for which robust biomarkers for early detection and tailored treatment are needed. Protein abundance measurements have so far not proven discriminative as PD biomarkers. Since alterations in protein structure reflect various functionally relevant molecular events, such as allostery, chemical modification, protein misfolding or molecular interaction, we have tested whether global analysis of protein structural changes is informative about PD pathophysiology and status and could form the basis of the new concept of structural biomarkers of disease. We applied limited proteolysis-mass spectrometry (LiP-MS) for the detection of global protein structural changes in cerebrospinal fluid (CSF) of PD patients and age-matched healthy individuals. Using linear modeling to correct for covariates, we identified 76 proteins as structurally altered in the CSF of patients with PD. We identified structural alterations in several proteins implicated in PD, many of which were also structurally altered in PD brain tissue suggesting that this approach provides insight into pathological mechanisms, although validation in independent cohorts is needed. Protein structural information from CSF outperformed protein abundance information in discriminating between healthy and PD subjects. Further, candidate structural biomarkers from our screen provided complementary information to CSF measures of the hallmark PD protein α-synuclein and thus improved the sensitivity and specificity of discriminating the healthy and PD states. Finally, we present the first analysis of inter-individual variability of a structural proteome in healthy humans, identifying biophysical and structural features of variable and invariable protein regions. Structurally variable protein regions show a greater propensity for protein-protein interaction and higher disorder than non-variable peptides. This dataset will be a valuable resource for structural biology and for future structure-based biomarker research. Our data suggest that global analyses of the human structural proteome will lead to the discovery of novel, structural biomarkers of disease and enables hypothesis-generation about the molecular events underlying disease processes.

Dataset Information

Endo-Lysosomal Proteins and Ubiquitin CSF Concentrations in Alzheimer’s and Parkinson’s Disease

Publications

Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets