Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD.

Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer's disease model.

Alzheimer's disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria.

Epigenetic conflict on a degenerating Y chromosome increases mutational burden in Drosophila males.

Large portions of eukaryotic genomes consist of transposable elements (TEs), and the establishment of transcription-repressing heterochromatin during early development safeguards genome integrity in Drosophila. Repeat-rich Y chromosomes can act as reservoirs for TEs ('toxic' Y effect), and incomplete epigenomic defenses during early development can lead to deleterious TE mobilization. Here, we contrast the dynamics of early TE activation in two Drosophila species with vastly different Y chromosomes of different ages.

De novo assembly of a young Drosophila Y chromosome using single-molecule sequencing and chromatin conformation capture.

While short-read sequencing technology has resulted in a sharp increase in the number of species with genome assemblies, these assemblies are typically highly fragmented. Repeats pose the largest challenge for reference genome assembly, and pericentromeric regions and the repeat-rich Y chromosome are typically ignored from sequencing projects. Here, we assemble the genome of Drosophila miranda using long reads for contig formation, chromatin interaction maps for scaffolding and short reads, and optical mapping and bacterial artificial chromosome (BAC) clone sequencing for consensus validation.

Alternative Splicing within and between Drosophila Species, Sexes, Tissues, and Developmental Stages.

Alternative pre-mRNA splicing ("AS") greatly expands proteome diversity, but little is known about the evolutionary landscape of AS in Drosophila and how it differs between embryonic and adult stages or males and females. Here we study the transcriptomes from several tissues and developmental stages in males and females from four species across the Drosophila genus. We find that 20-37% of multi-exon genes are alternatively spliced.