Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease.

TAR DNA binding protein-43 (TDP-43) is a key component in RNA splicing which plays a crucial role in the aging process. In neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, TDP-43 can be mutated, mislocalised out of the nucleus of neurons and glial cells and form cytoplasmic inclusions. These TDP-43 alterations can lead to its RNA splicing dysregulation and contribute to mis-splicing of various types of RNA, such as mRNA, microRNA, and circular RNA.

Cyclin F can alter the turnover of TDP-43.

Previously, we demonstrated that the SCF complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F.

Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.

The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g.

Post-translational modification analysis of Saccharomyces cerevisiae histone methylation enzymes reveals phosphorylation sites of regulatory potential.

Histone methylation is central to the regulation of eukaryotic transcription. In Saccharomyces cerevisiae, it is controlled by a system of four methyltransferases (Set1p, Set2p, Set5p, and Dot1p) and four demethylases (Jhd1p, Jhd2p, Rph1p, and Gis1p). While the histone targets for these enzymes are well characterized, the connection of the enzymes with the intracellular signaling network and thus their regulation is poorly understood; this also applies to all other eukaryotes.

Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents.

Background: Quaternary ammonium compounds are a large class of chemicals used for their antimicrobial and antistatic properties. Two common quaternary ammonium compounds, alkyldimethylbenzyl ammonium chloride (ADBAC) and didecyldimethyl ammonium chloride (DDAC), are combined in common cleaners and disinfectants. Introduction of a cleaner containing ADBAC+DDAC in the vivarium caused neural tube defects (NTDs) in mice and rats.