Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?
Abstract
:1. Introduction
2. Proteomic Methodology
2.1. Proteomic Profiling Using Mass Spectrometry
2.2. Sample Selection and Processing
2.3. Downstream Proteomic Data Analysis
3. Proteomic Studies in FTLD-TDP
3.1. Bulk Tissue
3.2. Isolated Tissue or Cellular Inclusions
3.3. Phosphoproteomics
3.4. Fluid Substrates
4. Converging Molecular Pathways in FTLD-TDP
4.1. RNA Metabolism
4.2. Neuroinflammation
4.3. Endolysosomal System
4.4. Cytoskeleton
4.5. Mitochondrial Functioning
4.6. Synaptic Functioning
5. Conclusions and Future Directions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALS | Amyotrophic lateral sclerosis |
C9orf72 | Chromosome 9 open reading frame 72 |
CHCHD | coiled-coil-helix-coiled-coil-helix domain |
CHMP2B | Charged multivesicular body protein 2B |
CSF | Cerebrospinal fluid |
CLTC | Clathrin heavy chain |
CTSD | Cathepsin D |
CSRP1 | Cysteine and glycine rich protein 1 |
CTTN | Cortactin |
TDP-43 | TAR DNA-binding protein 43 |
FTD | Frontotemporal dementia |
FTLD | Frontotemporal lobar degeneration |
GFAP | Glial fibrillary acidic protein |
GRN | Granulin precursor |
HEPACAM | Hepatic and glial cell adhesion molecule |
hnRNP | Heterogeneous ribonuclear protein |
LCM | Laser capture microdissection |
MAPT | Microtubule associated protein tau |
MS | Mass spectrometry |
MSN | Moesin |
NDRG2 | N-myc downstream-regulated gene 2 protein |
NDUF | NADH dehydrogenase (ubiquinone) proteins |
NPTX1 | Neuronal pentraxin 1 |
OPTN | Optineurin |
PGRN | Progranulin |
PHB | Prohibitin |
PPT1 | Palmitoyl-protein thioesterase 1 |
PRDX6 | Peroxiredoxin 6 |
PSF | PTB-associated splicing factor |
PTM | Posttranslational modification |
SEPT | Septin |
TARDBP | TAR DNA binding protein 43 |
TBK1 | TANK binding kinase 1 |
TIA1 | TIA1 cytotoxic granule associated RNA binding protein |
TMEM106B | Transmembrane protein 106B |
SILAC | Stable Isotope Labeling with Amino acids in Cell culture |
SNAP25 | Synaptosome associated protein 25 |
STXBP1 | Syntaxin binding protein 1 |
TREM2 | Triggering receptor expressed on myeloid cells 2 |
TUBA4A | Tubulin alpha 4a |
SQSTM1 | Sequestosome 1 |
UBQLN2 | Ubiquilin 2 |
UPS | Ubiquitin-proteasome system |
UQCR | Ubiquinol-cytochrome C reductase proteins |
VCP | Valosin containing protein |
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Study | Cases, Subtypes | FTLD Cases, N | Healthy Controls, N | Region | Method | DEP in FTLD vs. Controls, N | Upregulated Pathways | Downregulated Pathways |
---|---|---|---|---|---|---|---|---|
Bulk tissue | ||||||||
Umoh, et al., 2017 [38] | FTLD-TDP; ALS; ALS-FTD | 12 | 10 | Frontal cortex | MS, label-free (MaxLFQ) | 407 | RNA metabolism, neuro-inflammation, homeostatic processes, zinc ion binding | Mitochondrion, synapse, neuronal differentiation |
Andrés-Benito, et al., 2019 [39] | FTLD-TDP type B (C9orf72) | 19 | 14 | Frontal cortex | MS, label-free (Progenesis) | 130 | Neuroinflammation, apoptosis, metabolism, phagocytosis, endocytosis, oxidative stress | Mitochondrion, synapse, metabolism, microtubules |
Iridoy, et al., 2018 [40] | FTLD-TDP; ALS | 8 | 8 | Spinal cord | MS, label-free (Progenesis) | 52 | Mitochondrion, metabolism | Mitochondrion, protein kinase signaling |
Lachén-Montes, et al., 2019 [41] | FTLD-TDP; PSP | 4 | 4 | Olfactory bulb | MS, TMT | 28 | Cytoskeleton, apoptosis, protein synthesis | Vesicle trafficking, synapse, protein kinase signaling |
Isolated tissue or cellular inclusions | ||||||||
Gozal, et al., 2011 [42] | FTLD-TDP | 3 | 3 | Hippocampus, dentate gyrus | MS, label-free (SC) | 73 | Cytoskeleton, metabolism, oxidative stress, protein degradation | Mitochondrion, metabolism |
Gozal, et al., 2011 [43] | FTLD-TDP; AD | 10 | 10 | Frontal cortex, inclusions | MS; label-free (XIC) and CDIT a | 10 a | Cytoskeleton, glutamate transporter activity, cell adhesion | Synapse, metabolism |
Seyfried, et al., 2012 [32] | FTLD-TDP | 4 | 4 | Frontal cortex, inclusions | MS; SILAC and label-free (SC) | 21 | RNA metabolism, cyto-skeleton, mitochondrion, metabolism, endoplasmic reticulum, membrane/transport | - |
Laferrière, et al., 2019 [44] | FTLD-TDP types A, B, and C; ALS | 15 | 6 | Frontal cortex, inclusions | MS, label-free (SC) | 28 b | RNA metabolism, neuro-inflammation. protein degradation, cytoskeleton, mitochondrion, cell adhesion, lysosome | - |
Phosphoproteomics | ||||||||
Herszkowitz, et al., 2011 [45] | FTLD-TDP | 4 | 4 | Frontal cortex | IMAC; MS, label-free (SC) | 6 | Cytoskeleton | Microtubule, synapse, chaperones |
Functional Pathway | Umoh et al. [38] | Andrés- Benito et al. [39] | Iridoy et al. [40] | Lachén-Montes et al. [41] | Gozal et al. [42] | Gozal et al. [43] | Seyfried et al. [32] | Laferrière et al. [44] | Herszk-owitz et al. [45] | Overlapping Proteins /Protein Families | Validated Proteins |
---|---|---|---|---|---|---|---|---|---|---|---|
RNA metabolism | X | X | X | X | X | hnRNPs, CSRP1 | PSF | ||||
Neuroinflammation | X | X | X | X | X | X | GFAP, MSN, HEPACAM, PRDX6 | GFAP, MSN, HEPACAM | |||
Endolysosomal system | X | X | X | X | X | X | X | Annexins, Rabs, ASAH1, CLTC, CTSD, PPT1 | TPP1, ASAH1 | ||
Cytoskeleton | X | X | X | X | X | X | X | X | X | Septins, CTTN, GFAP, MSN | SEPT3, SEPT7, SEPT11, NDRG2 |
Mitochondrial functioning | X | X | X | X | X | X | Prohibitins, NDUFs, UQCRs, ATP5A1, | PHB1, PHB2 | |||
Synaptic functioning | X | X | X | X | X | X | X | Syntaxins, SNAP25, PRRT2 | SNAP25 |
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Mol, M.O.; Miedema, S.S.M.; van Swieten, J.C.; van Rooij, J.G.J.; Dopper, E.G.P. Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics? Int. J. Mol. Sci. 2021, 22, 10298. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910298
Mol MO, Miedema SSM, van Swieten JC, van Rooij JGJ, Dopper EGP. Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics? International Journal of Molecular Sciences. 2021; 22(19):10298. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910298
Chicago/Turabian StyleMol, Merel O., Suzanne S. M. Miedema, John C. van Swieten, Jeroen G. J. van Rooij, and Elise G. P. Dopper. 2021. "Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?" International Journal of Molecular Sciences 22, no. 19: 10298. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910298