Targeted RNA-seq of FTLD-TDP brain samples
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49322 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR7626320.fastq.gz | Fastqsanger.gz | |||
| ERR7626330.fastq.gz | Fastqsanger.gz | |||
| ERR7626321.fastq.gz | Fastqsanger.gz | |||
| ERR7626331.fastq.gz | Fastqsanger.gz | |||
| ERR7626312.fastq.gz | Fastqsanger.gz |
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Project description:UNC13A features a cryptic exon which is expressed upon loss of nuclear TDP-43. Here, we perform targeted RNA-seq on RNA extracted from 10 FTLD-TDP brain samples, and four control samples, enriching for the cryptic exon via nested PCR. Each FTLD-TDP sample is heterozygous for rs12973192. There are two fastqs for each sample. One uses a sequence-specific reverse transcription primer, and detects both the cryptic-containing and correctly spliced isoforms. The second uses random hexamer primer (with specificity derived from downstream PCR and second strand synthesis) - this approach only detects the isoform containing the cryptic. The fastq files provided are demultiplexed and adaptor trimmed. Unique molecular identifiers have been moved to each read name, after \"rbc:\" (random barcode).
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Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
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Project description:RNA extracted from human frontal cortex area 8, the main area afected in FTLD, of controls (n=10), sporadic FTLD-TDP (sFTLD) (n=10) and C9ORF72-familial FTLD (fFTLD) (n=10) samples were analyzed using the Affymetrix Clariom™ D Assay, human (Affymetrix ref.902923). The present study identifies the main gene deregulation between sporadic forms of FTLD-TDP (sFTLD) and the major and most common genetic cause of FTLD, the C9ORF72 repeat expansion (fFTLD), when compare with control samples.
2018-09-19 | E-MTAB-6189 | biostudies-arrayexpress
Project description:FTLD-U is the most common pathological correlate of the neurodegenerative dementia frontotemporal dementia; We used microarrays to perform global expression profiling of FTLD-U brain samples Experiment Overall Design: Postmortem brain samples were isolated from normal controls, FTLD-U patients with progranulin gene mutations (progranulin) and FTLD-U patients without progranulin gene mutations (sporadic). Regional dissections were carried out from frontal cortex, hippocampus, and cerebellum.
2008-10-26 | E-GEOD-13162 | biostudies-arrayexpress
Project description:FTLD-U is the most common pathological correlate of the neurodegenerative dementia frontotemporal dementia We used microarrays to perform global expression profiling of FTLD-U brain samples Keywords: disease
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Project description:Dominant mutations in unrelated genes cause fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and include VCP, which is associated with multisystem proteinopathy (MSP). Conditional inactivation of VCP in postnatal forebrain neurons (VCP cKO) caused cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, TDP-43 inclusions and hyperactivity. Quantitative proteomics and single nuclei RNA sequencing on VCP cKO brains identified synaptogenesis and the unfolded protein response as the most decreased and increased pathways respectively. Conditional expression of a single MSP disease mutation, VCP-R155C, in cortical neurons similarly recapitulated features of VCP inactivation and FTLD-TDP. Comparison of transcriptomic and proteomic datasets from genetically defined FTD patients revealed that profiles from GRN carriers were similar to VCP insufficiency. These data support a deficiency in VCP dependent functions as the pathogenic mechanism of FTLD-TDP and reveal an unexpected pathogenic similarity with progranulin deficiency. Enhancing VCP function may be therapeutic in MSP and related forms of FTLD-TDP.
2021-08-06 | PXD026685 | Pride
Project description:No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
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Project description:TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.
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Project description:FTLD is the third most common neurodegenerative condition, following only Alzheimer's and Parkinson's diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TDP-43 immunoreactivity. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryo-EM. Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of TMEM106B, a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.
2021-11-22 | MSV000088430 | MassIVE
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2018-10-10 | PXD007873 | Pride