Nucleosomes in gene regulation: theoretical approaches

This work reviews current theoretical approaches of biophysics and bioinformatics for the description of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from molecular-mechanistic and biological point of view. In addition to classical problems of this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials

Uncoupling of neuroinflammation from axonal degeneration in mice lacking the myelin protein tetraspanin-2

Deficiency of the major constituent of central nervous system (CNS) myelin, proteolipid protein (PLP), causes axonal pathology in spastic paraplegia type-2 patients and in Plp1null-mice but is compatible with almost normal myelination. These observations led us to speculate that PLP's role in myelination may be partly compensated for by other tetraspan proteins. Here, we demonstrate that the abundance of the structurally related tetraspanin-2 (TSPAN2) is highly increased in CNS myelin of Plp1null-mice. Unexpectedly, Tspan2null-mutant mice generated by homologous recombination in embryonic stem cells displayed low-grade activation of astrocytes and microglia in white matter tracts while they were fully myelinated and showed no signs of axonal degeneration. To determine overlapping functions of TSPAN2 and PLP, Tspan2null*Plp1null double-mutant mice were generated. Strikingly, the activation of astrocytes and microglia was strongly enhanced in Tspan2null*Plp1null double-mutants compared with either single-mutant, but the levels of dysmyelination and axonal degeneration were not increased. In this model, glial activation is thus unlikely to be caused by axonal pathology, and vice versa does not potentiate axonal degeneration. Our results support the concept that multiple myelin proteins have distinct roles in the long-term preservation of a healthy CNS, rather than in myelination per se