Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?

Mol, Merel O.; Miedema, Suzanne S M; Swieten, John C. van; Rooij, Jeroen G.J. van; Dopper, Elise G.P.

doi:10.3390/ijms221910298

Cited by 14 publications

(13 citation statements)

References 138 publications

(170 reference statements)

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“…To date, several genome-wide association and transcriptomic studies have identified susceptibility genes, implicating impairments in lysosomal autophagy and the immune system across the FTD spectrum [ 6 , 8 , 18 , 19 , 63 , 68 ]. A few studies have focussed on proteome changes in neuropathological subtypes, including FTD associated with TDP-43 pathology (FTD-TDP) [ 25 , 26 , 31 , 38 , 48 , 70 ], FUS pathology [ 43 ], and in the genetic subtype FTD-C9 [ 3 ]. However, a systematic proteomic analysis of dysregulated proteins and pathways in affected cell types in genetic FTD is lacking.…”

Section: Introductionmentioning

confidence: 99%

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

Miedema

Mol

Koopmans

et al. 2022

acta neuropathol commun

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Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer’s disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

Miedema

Mol

Koopmans

et al. 2022

acta neuropathol commun

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“…protein kinase C and casein kinase substrate in neurons 1, PACSIN1; proline rich transmembrane protein 2, PRRT2). 25,26,37 Both FTLD-tau and FTLD-TDP data sets were enriched for gene sets previously associated with Alzheimer's disease and Huntington's disease, suggesting dysregulated pathways common to neurodegenerative conditions, next to gene sets associated with oxidative phosphorylation (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Clusters of co-regulated proteins in brain cortex associate with fronto-temporal lobar degeneration

Bridel

Gils

Miedema

et al. 2022

Preprint

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Background Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified Cyclin-Dependent Kinase 5 (CDK5) and Polypyrimidine Tract Binding Protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation datasets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein expression levels, indicating pathological changes in FTD are not limited to neurons. Conclusions Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.

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“…How do the above-mentioned observations correspond to TDP-43 proteinopathies? First of all, many transcriptomic/proteomic analyses in patients with ALS–FTSD or TDP-43 proteinopathy animal models do not report parkin expression alterations [ 102 , 103 , 104 , 105 , 106 ]. These might be due to the fact that all “omic” results (RNAseq, microarrays, and proteomics) carry a bias, since they are not able to distinguish between healthy cells and those with TDP-43 pathology.…”

Section: Interwoven Relations Between Tdp-43 and Parkinmentioning

confidence: 99%

“…Another aspect complicating the situation is that TDP-43 regulates other mediators of mitophagy and autophagy, as reviewed in References [ 140 , 143 , 144 , 145 ]. Specifically, TDP-43 imbalance (downregulation or upregulation) has been observed to impair autophagy flux and disrupt autophagosome–lysosomal fusion [ 106 , 140 , 145 , 146 , 147 ]. For example, overexpression of pathogenic CTF TDP-25 in mice leads to autophagy reduction/stalling [ 148 ].…”

Section: Additional Mechanisms Of Tdp-43—mediated Mitochondrial Dysfunctionmentioning

confidence: 99%

Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

Gawęda-Walerych

Sitek

Narożańska

et al. 2021

Cells

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Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson’s disease (PD) caused by loss-of-function mutations in the PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases—especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.

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Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?

Cited by 14 publications

References 138 publications

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

Clusters of co-regulated proteins in brain cortex associate with fronto-temporal lobar degeneration

Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

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