PXD022872-2

PXD022872 is an original dataset announced via ProteomeXchange.

Title	GENETIC SUBTYPE- AND CELL TYPE-SPECIFIC PROTEIN SIGNATURES IN FRONTOTEMPORAL DEMENTIA
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:41:22.750.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Suzanne Miedema
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-02 08:17:38	ID requested
1	2023-03-11 02:58:13	announced
⏵ 2	2023-11-14 08:41:23	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Frontotemporal dementia

C9ORF72

GRN

MAPT

human brain proteomics

August B. Smit
contact affiliation	Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
contact email	guus.smit@vu.nl
lab head
Suzanne Miedema
contact affiliation	Vrije Universiteit Amsterdam
contact email	s.s.m.miedema@vu.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022872
     1. Label: PRIDE project
     2. Name: GENETIC SUBTYPE- AND CELL TYPE-SPECIFIC PROTEIN SIGNATURES IN FRONTOTEMPORAL DEMENTIA