Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation.

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants (SVs); however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs.

Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming.

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if aging-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state.

Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes.

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals.

14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.

Leucine-rich repeat kinase 2 (LRRK2) is a central player in cellular signaling and a significant contributor to Parkinson's disease (PD) pathogenesis. 14-3-3 proteins are essential regulators of LRRK2, modulating its activity. Here, we present the cryo- electron microscopy structure of the LRRK2:14-3-3 autoinhibitory complex, showing that a 14-3-3 dimer stabilizes an autoinhibited LRRK2 monomer by binding to key phosphorylation sites and the COR-A and COR-B subdomains within the Roc-COR GTPase domain of LRRK2.