Dataset Information

Identification of novel CSF biomarkers in GRN-associated frontotemporal dementia by proteomics

ABSTRACT: Frontotemporal dementia is the second most common form of presenile dementia and autosomal dominant inheritance is present in 20-30% of cases, with mutations in granulin (GRN) as a major cause. The exact pathophysiological mechanism by which GRN mutations lead to neurodegeneration is poorly understood. We aimed to identify novel cerebrospinal fluid (CSF) biomarkers in GRN-associated frontotemporal dementia using shotgun proteomics. We included CSF from presymptomatic and symptomatic GRN mutation carriers and healthy non-carriers (controls). We validated our discovery proteomics results in a large international cohort of GRN-mutation carriers and other forms of genetic FTD (C9orf72- and MAPT-mutation carriers) by parallel reaction monitoring.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Frontotemporal Dementia

SUBMITTER: Christoph Stingl

LAB HEAD: Theo M. Luider

PROVIDER: PXD012179 | Pride | 2019-04-29

REPOSITORIES: pride

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			Action	DRS
	180301OFes_JvS-1635-WP244-A05--PRM_031 (F137987).mzid.gz_180301OFes_JvS-1635-WP244-A05--PRM_031_(F137987).pride.mgf.gz	Mzid
	180301OFes_JvS-1635-WP244-A05--PRM_031 (F137987).pride.mztab.gz	Mztab
	180301OFes_JvS-1635-WP244-A05--PRM_031.raw	Raw
	180301OFes_JvS-1635-WP244-A05--PRM_031F137987.mzid.gz	Mzid
	180301OFes_JvS-1635-WP244-A05--PRM_031F137987.mzid.gz_180301OFes_JvS-1635-WP244-A05--PRM_031_F137987.MGF	Mzid

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Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.

van der Ende Emma L EL Meeter Lieke H LH Stingl Christoph C van Rooij Jeroen G J JGJ Stoop Marcel P MP Nijholt Diana A T DAT Sanchez-Valle Raquel R Graff Caroline C Öijerstedt Linn L Grossman Murray M McMillan Corey C Pijnenburg Yolande A L YAL Laforce Robert R Binetti Giuliano G Benussi Luisa L Ghidoni Roberta R Luider Theo M TM Seelaar Harro H van Swieten John C JC

Annals of clinical and translational neurology 20190307 4

<h4>Objective</h4>To identify novel CSF biomarkers in <i>GRN</i>-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS).<h4>Methods</h4>Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic <i>GRN</i> mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by ...[more]

PMID: 31019994

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Project description:Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices and an early age of onset. The disorder is highly heterogenic, comprising several genetic causes as well as a diverse phenotypic landscape of sporadic cases. Here we investigated the proteomic signatures of human brain frontal and temporal cortical lobes to identify key pathways involved in the three most frequent genetic subtypes of frontotemporal dementia. We included 38 patients with either an autosomal dominant repeat expansion in the C9ORF72 gene (n = 16), or a mutation in the GRN gene (n = 9) or the MAPT gene (n = 13), and 11 non-demented controls. Using data-independent quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for these genetic frontotemporal dementia subtypes compared to non-demented controls. Using published single cell RNA expression data for cell type enrichment we deduced the involvement of major brain cell types in driving these different protein signatures. Using gene ontology analysis, we identified distinct genetic subtype- and cell type-specific biological processes. In the GRN-mediated subtype, we observed higher protein expression related to immune processes, with a role for endothelial cells and astrocytes, and lower protein expression implicating mitochondrial dysregulation, primarily in neurons. In the MAPT-mediated subtype, we observed higher protein expression associated with dysregulation of RNA processing in multiple cell types, and lower protein expression implicating altered neuronal functioning via dysregulation of oligodendrocytes. Comparison of the MAPT-mediated frontotemporal dementia signature with one obtained from Alzheimer’s disease brains demonstrated only partial overlap in protein dysregulation, thus separating general neurodegenerative processes and highlighting the frontotemporal dementia-specific involvement of altered RNA processing and oligodendrocyte dysfunction. Taken together, our results indicate a role for different brain cell types and biological mechanisms in frontotemporal dementia, revealing both genetic subtype-specific processes, and processes shared with other neurodegenerative diseases such as Alzheimer’s disease.