TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Linking hnRNP Function to ALS and FTD Pathology

Following years of rapid progress identifying the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and related diseases such as frontotemporal dementia (FTD), remarkable consistencies have emerged pointing to perturbed biology of heterogeneous nuclear ribonucleoproteins (hnRNPs) as a central driver of pathobiology. To varying extents these RNA-binding proteins are deposited in pathological inclusions in affected tissues in ALS and FTD. Moreover, mutations in hnRNPs account for a significant number of familial cases of ALS and FTD. Here we review the normal function and potential pathogenic contribution of TDP-43, FUS, hnRNP A1, hnRNP A2B1, MATR3, and TIA1 to disease. We highlight recent evidence linking the low complexity sequence domains (LCDs) of these hnRNPs to the formation of membraneless organelles and discuss how alterations in the dynamics of these organelles could contribute to disease. In particular, we discuss the various roles of disease-associated hnRNPs in stress granule assembly and disassembly, and examine the emerging hypothesis that disease-causing mutations in these proteins lead to accumulation of persistent stress granules

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

Neuronal injury triggers robust responses from glial cells, including altered gene expression and enhanced phagocytic activity to ensure prompt removal of damaged neurons. The molecular underpinnings of glial responses to trauma remain unclear. Here, we find that the evolutionarily conserved insulin-like signaling (ILS) pathway promotes glial phagocytic clearance of degenerating axons in adult Drosophila. We find that the insulin-like receptor (InR) and downstream effector Akt1 are acutely activated in local ensheathing glia after axotomy and are required for proper clearance of axonal debris. InR/Akt1 activity, it is also essential for injury-induced activation of STAT92E and its transcriptional target draper, which encodes a conserved receptor essential for glial engulfment of degenerating axons. Increasing Draper levels in adult glia partially rescues delayed clearance of severed axons in glial InR-inhibited flies. We propose that ILS functions as a key post-injury communication relay to activate glial responses, including phagocytic activity

A Resource for Manipulating Gene Expression and Analyzing cis-Regulatory Modules in the Drosophila CNS

Here, we describe the embryonic central nervous system expression of 5,000 GAL4 lines made using molecularly defined cis-regulatory DNA inserted into a single attP genomic location. We document and annotate the patterns in early embryos when neurogenesis is at its peak, and in older embryos where there is maximal neuronal diversity and the first neural circuits are established. We note expression in other tissues, such as the lateral body wall (muscle, sensory neurons, and trachea) and viscera. Companion papers report on the adult brain and larval imaginal discs, and the integrated data sets are available online (http://www.janelia.org/gal4-gen1). This collection of embryonically expressed GAL4 lines will be valuable for determining neuronal morphology and function. The 1,862 lines expressed in small subsets of neurons (<20/segment) will be especially valuable for characterizing interneuronal diversity and function, because although interneurons comprise the majority of all central nervous system neurons, their gene expression profile and function remain virtually unexplored

The minimum amount of "matrix " needed for matrix-assisted pulsed laser deposition of biomolecules

The ability of matrix-assisted pulsed laser evaporation (MAPLE) technique to transfer and deposit high-quality thin organic, bioorganic, and composite films with minimum chemical modification of the target material has been utilized in numerous applications. One of the outstanding problems in MAPLE film deposition, however, is the presence of residual solvent (matrix) codeposited with the polymer material and adversely affecting the quality of the deposited films. In this work, we investigate the possibility of alleviating this problem by reducing the amount of matrix in the target. A series of coarse-grained molecular dynamics simulations are performed for a model lysozyme–water system, where the water serves the role of volatile “matrix” that drives the ejection of the biomolecules. The simulations reveal a remarkable ability of a small (5–10 wt %) amount of matrix to cause the ejection of intact bioorganic molecules. The results obtained for different laser fluences and water concentrations are used to establish a “processing map” of the regimes of molecular ejection in matrix-assisted pulsed laser deposition. The computational predictions are supported by the experimental observation of the ejection of intact lysozyme molecules from pressed lysozyme targets containing small amounts of residual water. The results of this study suggest a new approach for deposition of thin films of bioorganic molecules with minimum chemical modification of the molecular structure and minimum involvement of solvent into the deposition process