TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Фев. 26, 2025

The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. has been identified as risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate role in proteinopathy, we ablated TDP-43Q331K knock-in mouse line, which expresses an ALS-linked mutation at endogenous levels. We found that deficiency leads to glial activation, Purkinje cell loss, behavioral deficits mice without inducing typical pathology. Interestingly, ablation results significant body weight gain, increased fat deposition, hepatic triglyceride (TG) accumulation mice. In addition, lipidomic transcriptome analysis shows profound alteration lipid metabolism liver TDP-43Q331KTmem106b−/− Our studies reveal novel function provide new insights into their roles An unexpected obesity phenotype altered TMEM106B-deficient metabolism, providing

Язык: Английский

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From Omics to Multi-Omics: A Review of Advantages and Tradeoffs

Genes, Год журнала: 2024, Номер 15(12), С. 1551 - 1551

Опубликована: Ноя. 29, 2024

Bioinformatics is a rapidly evolving field charged with cataloging, disseminating, and analyzing biological data. started genomics, but while genomics focuses more narrowly on the genes comprising genome, bioinformatics now encompasses much broader range of omics technologies. Overcoming barriers scale effort that plagued earlier sequencing methods, adopted an ambitious strategy involving high-throughput highly automated assays. However, as list technologies continues to grow, has changed in two fundamental ways. Despite enormous success expanding our understanding world, failure bulk methods account for biologically important variability among cells same or different type led major shift toward single-cell spatially resolved which attempt disentangle conflicting signals contained heterogeneous samples by examining individual cell clusters. The second been integrate classes data single multimodal analysis identify patterns bridge layers. For example, unraveling cause disease may reveal metabolite deficiency caused enzyme be phosphorylated because gene not expressed due aberrant methylation result rare germline variant. Conclusions: There fine line between superficial paralysis, like detective novel, multi-omics increasingly provides clues we need, if only are able see them.

Язык: Английский

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Lipidomics reveals cell specific changes during pluripotent differentiation to neural and mesodermal lineages

Molecular Omics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Lipidomic analyses of induced pluripotent stem cells at critical stages differentiation toward neural or mesodermal fates illustrate unique species and class-based fluctuations.

Язык: Английский

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Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells

Translational Neurodegeneration, Год журнала: 2025, Номер 14(1)

Опубликована: Апрель 16, 2025

Abstract Heterozygous mutations in GRN gene lead to insufficient levels of the progranulin (PGRN) protein, resulting frontotemporal dementia (FTD) with TAR DNA-binding protein 43 (TDP-43) inclusions, classified pathologically as lobar degeneration (FTLD-TDP). Homozygous are exceedingly rare and cause neuronal ceroid lipofuscinosis 11, a lysosomal storage disease onset young adulthood, or an FTD syndrome late-onset manifestations. In this review, we highlight broad spectrum clinical phenotypes associated PGRN deficiency, including primary progressive aphasia behavioral variant dementia. We explore these alongside relevant rodent vitro human models, ranging from induced pluripotent stem cell-derived neural progenitors, neurons, microglia, astrocytes genetically engineered heterotypic organoids containing both neurons astrocytes. summarize advantages limitations models recapitulating main FTLD- hallmarks, highlighting role non-cell-autonomous mechanisms formation TDP-43 pathology, neuroinflammation, neurodegeneration. Data obtained patients’ brain tissues biofluids, parallel single-cell transcriptomics, demonstrate complexity interactions among highly heterogeneous cellular clusters present brain, astrocytes, oligodendroglia, endothelial cells, pericytes. Emerging evidence has revealed that deficiency is cell cluster-specific, often conserved, genetic molecular central nervous system. focus on how distinct populations their dysfunctional crosstalk contribute neurodegeneration neuroinflammation FTD- . Specifically, characterize lipid droplet-accumulating microglia alterations myelin content dysfunction caused by deficiency. Additionally, consider deregulation glia-neuron communication affects exchange organelles such mitochondria, removal excess toxic products aggregates, PGRN-related

Язык: Английский

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Benchmarking SILAC Proteomics Workflows and Data Analysis Platforms

Molecular & Cellular Proteomics, Год журнала: 2025, Номер unknown, С. 100980 - 100980

Опубликована: Апрель 1, 2025

Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful metabolic technique with broad applications and various study designs. SILAC proteomics relies on the accurate identification quantification of all isotopic versions proteins peptides during both data acquisition analysis. However, comprehensive comparison evaluation analysis platforms currently lacking. To address this critical gap offer practical guidelines for analysis, we designed benchmarking pipeline to evaluate vitro workflows commonly used software. Ten different using five software packages (MaxQuant, Proteome Discoverer, FragPipe, DIA-NN, Spectronaut) were evaluated static dynamic DDA DIA methods. For benchmarking, in-house generated repository datasets from HeLa neuron samples. We assessed twelve performance metrics including identification, quantification, accuracy, precision, reproducibility, filtering criteria, missing values, false discovery rate, protein half-life measurement, completeness, unique features, speed Each method/software has its strengths weaknesses when these metrics. Most reaches range limit 100 folds light/heavy ratios. do not recommend Discoverer despite wide use label-free proteomics. achieve greater confidence researchers could more than one analyze same dataset cross-validation. In summary, offers first systematic platforms, providing support decision-making design

Язык: Английский

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Celebrating Women in Proteomics and Metabolomics

Journal of Proteome Research, Год журнала: 2024, Номер 23(8), С. 2675 - 2679

Опубликована: Авг. 2, 2024

Язык: Английский

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