Expression data from postmortem human brain samples with and without FTLD-U
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE13162 | GEO | 2008/10/11
SECONDARY ACCESSION(S): PRJNA109627
REPOSITORIES: GEO
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Project description:Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathological finding characterizing affected neurons in most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). At least four different subtypes of FTLD-TDP have been described, based on the morphology and neuroanatomical distribution of pathological TDP-43 accumulations. To understand the molecular basis of this heterogeneity that correlates with clinical presentations, we developed SarkoSpin, a new method for the biochemical isolation of pathological TDP-43 from complex tissues. Using postmortem samples of 79 patients and controls, we show that SarkoSpin allows the physical separation of pTDP-43 from ~99.8% of total proteins, including the extreme bulk of physiological TDP-43. Pathological TDP-43 extracted from different disease subtypes forms large and buoyant assemblies of distinct densities and 3-dimentional shapes that correlate with specific neuropathological classifications.
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Project description:A mild olfactory dysfunction has been observed in frontotemporal dementias (FTD). However, the underlying molecular mechanisms associated to this deficit are poorly understood. Here, we applied mass spectrometry-based quantitative proteomics to analyse pathological effects on the olfactory bulb (OB) from progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration TDP43 proteinopathy (FTLD-TDP) subjects
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Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.
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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:Frontotemporal dementia (FTD) is the most common form of dementia after Alzheimer's disease and results from frontotemporal lobar degeneration (FTLD). The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins1. In the majority of cases, the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterising different FTLD subtypes2,3. The presence, identities and structures of amyloid filaments in the remaining ~10% of FTLD cases are unknown, but are widely believed to be composed of the protein fused in sarcoma (FUS). As such, these cases are commonly referred to as FTLD-FUS. Here, we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Unexpectedly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15), rather than of FUS itself. The filament fold is formed from residues 7 to 99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, who also showed changes associated with amyotrophic lateral sclerosis (ALS), suggesting that TAF15 proteinopathy may underlie a disease spectrum of FTLD and ALS. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
2023-12-07 | PXD044821 | Pride
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.
2021-06-16 | GSE178257 | GEO