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Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology

ABSTRACT: Background Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by language deficits due to severe temporal lobe degeneration. The consistent neuropathological diagnosis is FTD-TDP subtype C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. Methods We carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTD and Alzheimer’s disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein-protein interactions (PPI). Results Of the total 5,354 quantified proteins, 151 showed differential abundance (FDR<1%) in SD patients. Seventy-two proteins were previously found altered with the same directional change in at least one FTD/AD proteomic study, while 79 proteins were considered as showing potentially SD specific dysregulation. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding– the cadherin-catenin complex. Multiple proteins in this complex showed strong and apparent specific upregulation in SD, including β-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2). Conclusions We discovered an increase of cell adhesion proteins in SD specifically constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further validation is warranted, we anticipate that these findings will help unravel the disease processes underlying SD.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Frontotemporal Dementia

SUBMITTER: Suzanne Miedema

LAB HEAD: August B. Smit

PROVIDER: PXD033060 | Pride | 2023-03-10

REPOSITORIES: Pride

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Project description:Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less-known. We found that an epigenetic and energetic agent, acetyl-L-carnitine (LAC, oral administration), rapidly rescued the depressive- and central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line (FSL) rats. After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not respond (nrFSL). RNAseq for the ventral dentate-gyrus (vDG), a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment-resistance in nrFSL shows a new gene profile, including the metabolic regulator factors Elovl7 and Cyb5r2 and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglycemia.tance in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as factor to be considered for the development of better therapeutics. Agents, like LAC, which regulate metabolic factors and reduce glutamate overflow, could rapidly ameliorate depression and could also be considered for treatment of insulin-resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology. Ventral dentate gyrus RNA from 3 biological replicates per group (vehicle-FRL, vehicle-FSL, LAC-treated not-responder FSL, LAC-treated responder FSL, all males) was used for library prep (TruSeq Stranded Total RNA with Ribo-Zero Human/Mouse/Rat) and sequenced on Illumina HiSeq2500 at the Genomic Core facility at The Rockefeller University. Each sample was provided with a unique adapter and all samples were put in the same pool and run in multiple lanes to control for lane effects with a sequencing depth of about 30M (100bp, single).

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Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology

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