Synaptic vesicle characterization of iPSC-derived dopaminergic neurons provides insight into distinct secretory vesicle pools.

The dysfunction of dopaminergic (DA) neurons is central to Parkinson's disease. Distinct synaptic vesicle (SV) populations, differing in neurotransmitter content (dopamine vs. glutamate), may vary due to differences in trafficking and exocytosis.

Fortilin binds CTNNA3 and protects it against phosphorylation, ubiquitination, and proteasomal degradation to guard cells against apoptosis.

Fortilin, a 172-amino acid polypeptide, is a multifunctional protein that interacts with various protein molecules to regulate their functions. Although fortilin has been shown to interact with cytoskeleton proteins such as tubulin and actin, its interactions with the components of adherens junctions remained unknown. Using co-immunoprecipitation western blot analyses, the proximity ligation assay, microscale thermophoresis, and biolayer interferometry, we here show that fortilin specifically interacts with CTNNA3 (α-T-catenin), but not with CTNNA1, CTNNA2, or CTNNB.

Roles for primary cilia in synapses and neurological disorders.

The role of primary cilia has recently garnered significant attention in the field of neurodegeneration. This review explores the diversity of primary cilia in the mature brain and their interrelationships with a multitude of cellular structures, including axons and synapses. Importantly, an overview of the growing prominence of ciliary-related dysfunctions in neurodegenerative diseases is summarized, with a special emphasis on Parkinson's disease (PD) and neuropsychiatric disorders.

Bridge-like lipid transfer protein 3A (BLTP3A) is associated with membranes of the late endocytic pathway and is an effector of CASM.

Recent studies have identified a family of rod-shaped proteins which includes VPS13 and ATG2 and are thought to mediate unidirectional lipid transport at intracellular membrane contacts by a bridge-like mechanism. Here, we show that one such protein, BLTP3A/UHRF1BP1, associates with VAMP7-positive vesicles via its C-terminal region and anchors them to lysosomes via the binding of its chorein domain containing N-terminal region to Rab7. Upon damage of lysosomal membranes and resulting mATG8 recruitment to their surface by CASM, BLTP3A first dissociates from lysosomes but then reassociates with them via an interaction of its LIR motif with mATG8.

Overlapping role of synaptophysin and synaptogyrin family proteins in determining the small size of synaptic vesicles.

Members of the synaptophysin and synaptogyrin family are vesicle proteins with four transmembrane domains. In spite of their abundance in synaptic vesicle (SV) membranes, their role remains elusive and only mild defects at the cellular and organismal level are observed in mice lacking one or more family members. Here, we show that coexpression with synapsin in fibroblasts of each of the four brain-enriched members of this family-synaptophysin, synaptoporin, synaptogyrin 1, and synaptogyrin 3-is sufficient to generate clusters of small vesicles in the same size range of SVs.

Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons.

Synaptojanin-1 (SJ1) is a major neuronal-enriched PI(4, 5)P 4- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1KI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function.

Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons.

Synaptojanin-1 (SJ1) is a major neuronal-enriched PI(4,5)P 4- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1KI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function.

A Commentary on the Effect of Targeted Temperature Management in Patients Resuscitated from Cardiac Arrest.

The members of the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force have written a comprehensive summary of trials of the effectiveness of induced hypothermia (IH) or targeted temperature management (TTM) in comatose patients after cardiac arrest (CA). However, in-depth analysis of these studies is incomplete, especially since there was no significant difference in primary outcome between hypothermia versus normothermia in the recently reported TTM2 trial. We critically appraise trials of IH/TTM versus normothermia to characterize reasons for the lack of treatment effect, based on a previously published framework for what to consider when the primary outcome fails.

MicroRNAs in Inflammatory Bowel Disease and Its Complications.

Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD.

Centronuclear Myopathy Caused by Defective Membrane Remodelling of Dynamin 2 and BIN1 Variants.

Centronuclear myopathy (CNM) is a congenital myopathy characterised by centralised nuclei in skeletal myofibers. T-tubules, sarcolemmal invaginations required for excitation-contraction coupling, are disorganised in the skeletal muscles of CNM patients. Previous studies showed that various endocytic proteins are involved in T-tubule biogenesis and their dysfunction is tightly associated with CNM pathogenesis.

Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation.

Fortilin is a 172-amino acid multifunctional protein present in both intra- and extracellular spaces. Although fortilin binds and regulates various cellular proteins, the biological role of extracellular fortilin remains unknown. Here we report that fortilin specifically interacts with TGF-β1 and prevents it from activating the TGF-β1 signaling pathway.

A pressure-induced ratiometric signalling chemosensor: a case of helical anthracenes.

One of the helical anthracenes, [4]HA, in which two fused anthracene ends are spatially arranged top and bottom, exhibits a ratiometric fluorescence response due to the hydrostatic pressure-dependent intramolecular [4+4] photocyclodimerization. This ratiometric signalling comes from the formation of an intramolecular stacked species and its subsequent photoreaction upon hydrostatic pressurization. The ratiometric indexes as a function of hydrostatic pressure may enable us to quantify an unknown pressure in solutions.

Imaging-based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy.

A centronuclear myopathy (CNM) is a group of inherited congenital diseases showing clinically progressive muscle weakness associated with the presence of centralized myonuclei, diagnosed by genetic testing and muscle biopsy. The gene encoding dynamin 2, DNM2, has been identified as a causative gene for an autosomal dominant form of CNM. However, the information of a DNM2 variant alone is not always sufficient to gain a definitive diagnosis as the pathogenicity of many gene variants is currently unknown.

Fortilin inhibits p53, halts cardiomyocyte apoptosis, and protects the heart against heart failure.

Heart failure (HF) has reached epidemic proportions in developed countries, affecting over 20 million people worldwide. Despite modern medical and device therapies, 60-70% of HF patients still die within 5 years of diagnosis as it relentlessly progresses through pervasive apoptotic loss of cardiomyocytes. Although fortilin, a 172-amino-acid anti-p53 molecule, is one of the most expressed proteins in the heart, its precise role there has remained unknown.

Expression and purification of a cleavable recombinant fortilin from Escherichia coli for structure activity studies.

Complications related to atherosclerosis account for approximately 1 in 4 deaths in the United States and treatment has focused on lowering serum LDL-cholesterol levels with statins. However, approximately 50% of those diagnosed with atherosclerosis have blood cholesterol levels within normal parameters. Human fortilin is an anti-apoptotic protein and a factor in macrophage-mediated atherosclerosis and is hypothesized to protect inflammatory macrophages from apoptosis, leading to subsequent cardiac pathogenesis.

A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm.

[Figure: see text].

Dynamin 2 and BAR domain protein pacsin 2 cooperatively regulate formation and maturation of podosomes.

Podosomes are actin-rich adhesion structures formed in a variety of cell types, such as monocytic cells or cancer cells, to facilitate attachment to and degradation of the extracellular matrix (ECM). Previous studies showed that dynamin 2, a large GTPase involved in membrane remodeling and actin organization, is required for podosome function. However, precise roles of dynamin 2 at the podosomes remain to be elucidated.

Construction of Helical Structures with Multiple Fused Anthracenes: Structures and Properties of Long Expanded Helicenes.

Invited for the cover of this issue is Shinji Toyota and co-workers at Tokyo Institute of Technology and Okayama University of Science. The image depicts a spirally rising dragon to represent the helical molecular structures in the manuscript. Read the full text of the article at 10.

Construction of Helical Structures with Multiple Fused Anthracenes: Structures and Properties of Long Expanded Helicenes.

Polycyclic aromatic compounds consisting of four or five fused anthracene units were synthesized by PtCl -catalyzed cycloisomerization as novel long expanded helicenes. These compounds have helical structures with significant stacking of the terminal anthracene moieties at 0.33 nm interlayer distance.

Mutant BIN1-Dynamin 2 complexes dysregulate membrane remodeling in the pathogenesis of centronuclear myopathy.

Membrane remodeling is required for dynamic cellular processes such as cell division, polarization, and motility. BAR domain proteins and dynamins are key molecules in membrane remodeling that work together for membrane deformation and fission. In striated muscles, sarcolemmal invaginations termed T-tubules are required for excitation-contraction coupling.

Internalization of AMPA-type Glutamate Receptor in the MIN6 Pancreatic β-cell Line.

The activity of AMPA-type glutamate receptor is involved in insulin release from pancreatic β-cells. However, the mechanism and dynamics that underlie AMPA receptor-mediated insulin release in β-cells is largely unknown. Here, we show that AMPA induces internalization of glutamate receptor 2/3 (GluR2/3), AMPA receptor subtype, in the mouse β-cell line MIN6.

Multiple Fused Anthracenes as Helical Polycyclic Aromatic Hydrocarbon Motif for Chiroptical Performance Enhancement.

Polycyclic aromatic hydrocarbons consisting of three fused anthracene units were designed as new π-conjugated compounds having helical structures. These expanded helicenes were synthesized by Pt-catalyzed cycloisomerization of the corresponding ethynyl-substituted precursors. The nonplanar and helical structure was confirmed by X-ray analysis and DFT calculations, and the barrier to helical inversion was estimated to be 34 kJ mol .