SUMMARY Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller Dieker Syndrome (MDS) is the most severe form of the disease. In this study, to investigate effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS induced pluripotent stem cells (iPSCs) using timelapse imaging, immunostaining, and single cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion, and severe apoptosis of the founder neuroepithelial stem cells accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study therefore deepens understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling human neurodevelopmental disorders.

Biochemical and structural analysis of two features of kinase structure, the “R-spine” and “Shell,” afford a detailed insight into the regulation of eukaryotic protein kinases.

No abstract

Parkinson’s disease is associated with the aberrant aggregation of α-synuclein. Although the causes of this process are still unclear, post-translational modifications of α-synuclein are likely to play a modulatory role. Since α-synuclein is constitutively N-terminally acetylated, we investigated how this post-translational modification alters the aggregation behavior of this protein. By applying a three-pronged aggregation kinetics approach, we observed that N-terminal acetylation results in a reduced rate of lipid-induced aggregation and slows down both elongation and fibril-catalyzed aggregate proliferation. An analysis of the amyloid fibrils produced by the aggregation process revealed different morphologies for the acetylated and non-acetylated forms in both lipid-induced aggregation and seed-induced aggregation assays. In addition, we found that fibrils formed by acetylated α-synuclein exhibit a lower β-sheet content. These findings indicate that N-terminal acetylation of α-synuclein alters its lipid-dependent aggregation behavior, reduces its rate of in vitro aggregation, and affects the structural properties of its fibrillar aggregates.

No abstract