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Biology subjects

Bos, I.

Publications and source records attributed to Bos, I..

3 recordsLinked to original sources

The nuclear lamin network passively responds to both active or passive cell movement through confinements

Physical models of cell motility rely mostly on cytoskeletal dynamical assembly. However, when cells move through the complex 3D environment of living tissues, they have to squeeze their nucleus that is stiffer than the rest of the cell. The lamin network, organised as a shell right underneath the nuclear membrane, contributes to the nuclear integrity and stiffness. Yet, its response during squeezed cell motility has never been fully characterised. As a result, up to now, the interpretations on the lamin response mechanism are mainly speculative. Here, we quantitatively map the lamin A/C distribution in both a microfluidic migration device and a microfluidic aspiration device. In the first case, the cell is actively involved in translocating the nucleus through the constriction, while in the second case, the cell behaves as a passive object that is pushed through the constriction by an external pressure. Using a quantitative description of the lamin shell response based on mass conservation arguments applied on the fluorescence signal of lamin, we show that in both cases of migration and aspiration, the response of the lamin network is passive. In this way, our results not only further elucidate the lamin response mechanism, but also allow to distinguish this passive deformation response from other active responses that may occur when the nucleus is squeezed through constrictions.

biophysics↗

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimers disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

genomics↗

Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Alzheimers disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimers Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (A{beta}) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A{beta}42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A{beta}38 and CSF-A{beta}40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A{beta} and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

genomics↗